Cd73 compounds

ABSTRACT

The present disclosure provides pyrimidine dione compounds, and pharmaceutical compositions thereof, for treating cancer, including solid tumors. The compounds can be used alone or in combination with other anti-cancer agents.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 63/018,774, filed on May 1, 2020, and ofU.S. Provisional Application No. 63/149,803, filed on Feb. 16, 2021,which are hereby incorporated herein by reference in their entiretiesfor all purposes.

BACKGROUND OF THE INVENTION

The glycosyl-phosphatidylinositol-anchored CD73 antigen (also known asCluster of Differentiation 73, ecto-5 ‘-nucleotidase, ecto-5’-NT, 5′-NT,and NTSE) is considered the rate-limiting enzyme in the generation ofextracellular adenosine (Stagg J, Smyth M J. Extracellular adenosinetriphosphate and adenosine in cancer. Oncogene. 2010; 29:5346-58.doi:10.1038/onc.2010.292). CD73 is a 70-kDa glycosylphosphatidylinositol(GPI)-anchored protein normally expressed on endothelial cells andsubsets of hematopoietic cells. CD73, together with CD39, regulatesadenosine triphosphate (ATP) metabolism. CD39 (NTPDase-1) converts ATPinto AMP, with only trace amounts of ADP being released, while CD73catalyzes the conversion of AMP to adenosine (Ado).

Extracellular Ado accumulates in cancerous tissues and constitutes animportant mechanism of tumor immune escape. Among other effects,tumor-derived Ado profoundly inhibits infiltrating effector T cells. ATPdegradation into Ado through CD39 and CD73 co-expressed on murine Treg(regulatory CD4+ T cells) has been shown as responsible for tumorimmunosuppression.

CD73 can be found constitutively expressed at high levels on varioustypes of cancer cells. CD73-generated adenosine is assumed to suppressadaptive anti-tumor immune responses thereby promoting tumor growth andmetastasis. And studies in animal models have shown that blockade ofCD73 activity suppresses tumor growth and prolongs survival by promotinganti-tumor adaptive immunity (Forte et al. (2012) J Immunol.189(5):2226-33). Given the need for cancer treatments, new compositionsand methods for regulating CD73 activity and related therapeutic agentsis needed. This disclosure meets this and other needs.

BRIEF SUMMARY OF THE INVENTION

In one embodiment, the present disclosure provides a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —C₁₋₆alkyl-O—C₁₋₆alkyl,        —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-O—, —C₃₋₇cycloalkyl-O—,        —O—C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl-C₁₋₃alkyl, —S(═O)₂—,        —S(═O)₂CH₂—, —CH₂S(═O)₂—, —N(R^(a))—, —N(R^(a))CH₂—,        —C₁₋₆alkyl-N(R^(b))—, —C₃₋₇cycloalkyl-N(R^(b))—,        —N(R^(a))C(═O)—, —C₁₋₃alkylN(R^(a))C(═O)—,        heterocycloalkyl-C(═O)—, heterocycloalkyl-N(H)C(═O)—,        heterocycloalkyl, heterocycloalkyl-C₁₋₆alkyl-O—, or        heterocycloalkyl-O—, wherein each alkyl, cycloalkyl, or        heterocycloalkyl is optionally substituted with one to four        halogens and is further optionally substituted with one or two        groups independently selected from —CN, —C₁₋₃alkyl and        —C₁₋₃haloalkyl;    -   one or two of Z¹, Z² and Z³ is CR² and the remaining one or two        of Z¹, Z², and Z³ is N;    -   one of W¹ and W² is N and the other is C;    -   R¹ is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl,        —C₁₋₆alkyl-C₆₋₁₂aryl, —C₁₋₆alkyl-heteroaryl, heterocycloalkyl,        heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl,        cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally        substituted with one to three halogens and is further optionally        substituted with one or two R³;    -   R² is each independently hydrogen, halogen, —CN, —C₁₋₆alkyl,        —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),        —C(═O)heterocycloalkyl, —C(═O)N(R^(b))C₆₋₁₂aryl,        —C(═O)N(R^(b))heteroaryl, —C(═O)N(R^(b))(R^(b)),        —C₁₋₆alkyl-S(═O)₂C₆₋₁₂aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl,        heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl is optionally substituted        with one to three halogens and is further optionally substituted        with one to three R⁴;    -   R³ is halogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl,        —C₁₋₃alkyl-C₃₋₇cycloalkyl, —C₁₋₃alkyl-heterocycloalkyl,        —N(R^(b))(R^(b)), —N(H)C(═O)O—R^(c), —C(═O)N(R^(b))(R^(b)),        —C(═O)OC₁₋₆alkyl, —C(═O)OC₁₋₆alkylC₆₋₁₂aryl, —C(═O)C₁₋₃alkyl,        —C(═O)C₃₋₇cycloalkyl, —C(═O)heterocycloalkyl,        —OC(═O)heterocycloalkyl, —OC(═O)N(H)C₁₋₆alkyl,        —OC(═O)N(H)C₃₋₇cycloalkyl, —OC(═O)OC₁₋₆alkyl,        —OC(═O)N(H)C₆₋₁₂aryl, or —OR′, wherein each alkyl, cycloalkyl,        heterocycloalkyl, or aryl is optionally substituted with one to        three halogens and is further optionally substituted with one or        two 12′;    -   R⁴ is halogen, —CN, —OR′, —C₁₋₆alkyl, —N(R^(b))(R^(b)), or        —C₁₋₆haloalkyl;    -   R^(a) is each independently hydrogen, or —C₁₋₃alkyl;    -   R^(b) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₁₋₆alkyl-C₃₋₇cycloalkyl,        —C₃₋₇cycloalkyl-C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —C₃₋₇halocycloalkyl, or —C(═O)C₁₋₆alkyl; and R^(c) is each        independently hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,        —C₃₋₇cycloalkyl, —C₁₋₃alkyl-C₃₋₇cycloalkyl,        —C₁₋₃alkyl-C₃₋₇cyclohaloalkyl, —OC₁₋₆alkyl, or        —C₃₋₇halocycloalkyl; and    -   wherein each heterocycloalkyl or heteroaryl bears one to four        heteroatoms each independently selected from N, O, and S;    -   wherein each heterocycloalkyl has 4 to 15 ring members; and    -   wherein each heteroaryl has 5 to 15 ring members.

In another embodiment, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —C₁₋₆alkyl-O—C₁₋₆alkyl,        —O—C₁₋₆alkyl, —C₃₋₇cycloalkyl-O—, —O—C₃₋₇cycloalkyl,        —C₃₋₇cycloalkyl-C₁₋₃alkyl-, —S(═O)₂—, —S(═O)₂CH₂—, —CH₂S(═O)₂—,        —N(R^(a))—, —N(R^(a))CH₂—, —C₁₋₆alkyl-N(R^(b))—,        —C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—,        C₁₋₃alkylN(R^(a))C(═O)—, heterocycloalkyl-C(═O)—,        heterocycloalkyl or heterocycloalkyl-O—, wherein each alkyl,        cycloalkyl, or heterocycloalkyl is optionally substituted with        one to four halogens and is further optionally substituted with        one or two groups independently selected from —CN and        —C₁₋₃alkyl;    -   one or two of Z¹, Z² and Z³ is CR² and the remaining one or two        of Z¹, Z², and Z³ is N;    -   one of W¹ and W² is N and the other is C;    -   R¹ is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl,        heterocycloalkyl, heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein        each alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is        optionally substituted with one to three halogens and is further        optionally substituted with one or two R³;    -   R² is each independently hydrogen, halogen, —CN, —C₁₋₆alkyl,        —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),        —C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))heteroaryl,        —C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl,        —N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl,        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl is optionally substituted with one to three halogens        and is further optionally substituted with one to three R⁴;    -   R³ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —N(R^(b))(R^(b)), —C(═O)OC₁₋₆alkyl, —OC(═O)N(H)C₁₋₆alkyl,        —OC(═O)OC₁₋₆alkyl, or —OR′;    -   R⁴ is halogen, —CN, —OR′, —C₁₋₆alkyl, —N(R^(b))(R^(b)), or        —C₁₋₆haloalkyl;    -   R^(a) is each independently hydrogen, or —C₁₋₃alkyl;    -   R^(b) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl,        —C₃₋₇halocycloalkyl, or —C(═O)C₁₋₆alkyl; and    -   R^(c) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl, or —C₃₋₇halocycloalkyl; and    -   wherein each heterocycloalkyl or heteroaryl bears one to four        heteroatoms each independently selected from N, O, and S;    -   wherein each heterocycloalkyl has 4 to 10 ring members; and    -   wherein each heteroaryl has 5 to 10 ring members.

In another embodiment, the present disclosure provides a pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or excipient.

In another embodiment, the present disclosure provides a method ofinhibiting CD73 in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of the present disclosure.

In another embodiment, the present disclosure provides a method oftreating cancer in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of the present disclosure.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“Alkyl” is a linear or branched saturated monovalent hydrocarbon. Forexample, an alkyl group can have 1 to 18 carbon atoms (i.e., C₁₋₁₈alkyl)or 1 to 8 carbon atoms (i.e., C₁₋₈ alkyl) or 1 to 6 carbon atoms (i.e.,C₁₋₆alkyl) or 1 to 4 carbon atoms (i.e., C₁₋₄alkyl). Examples of alkylgroups include, but are not limited to, methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), and3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃. Other alkyl groups includeheptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadecyl, hexadecyl,heptadecyl and octadecyl.

“Alkylene” refers to a straight or branched, saturated, aliphaticradical having the number of carbon atoms indicated, and linking atleast two other groups, i.e., a divalent hydrocarbon radical. The twomoieties linked to the alkylene can be linked to the same atom ordifferent atoms of the alkylene group. For instance, a straight chainalkylene can be the bivalent radical of —(CH₂)_(n)—, where n is 1, 2, 3,4, 5 or 6. Representative alkylene groups include, but are not limitedto, methylene, ethylene, propylene, isopropylene, butylene, isobutylene,sec-butylene, pentylene and hexylene. Alkylene groups can be substitutedor unsubstituted.

“Alkenyl” refers to a straight chain or branched hydrocarbon having atleast 2 carbon atoms and at least one double bond. Alkenyl can includeany number of carbons, such as C₂, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₂₋₇, C₂₋₈,C₂₋₉, C₂₋₁₀, C₃, C₃₋₄, C₃₋₅, C₃₋₆, C₄, C₄₋₅, C₄₋₆, C₅, C₅₋₆ and C₆.

Alkenyl groups can have any suitable number of double bonds, including,but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groupsinclude, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl,1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl,isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl,2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substitutedor unsubstituted.

“Alkynyl” refers to either a straight chain or branched hydrocarbonhaving at least 2 carbon atoms and at least one triple bond. Alkynyl caninclude any number of carbons, such as C₂, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₂₋₇,C₂₋₈, C₂₋₉, C₂₋₁₀, C₃, C₃₋₄, C₃₋₅, C₃₋₆, C₄, C₄₋₅, C₄₋₆, C₅, C₅₋₆, andC₆. Examples of alkynyl groups include, but are not limited to,acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl,2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl,2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl,2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substitutedor unsubstituted.

“Alkoxy” refers to an alkyl group having an oxygen atom that connectsthe alkyl group to the point of attachment: alkyl-O—. As for alkylgroup, alkoxy groups can have any suitable number of carbon atoms, suchas C₁₋₆. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy,pentoxy, hexoxy, etc. The alkoxy groups can be further substituted witha variety of substituents described within. Alkoxy groups can besubstituted or unsubstituted.

“Alkoxyalkyl” refers an alkoxy group linked to an alkyl group which islinked to the remainder of the compound such that the alkyl group isdivalent. Alkoxyalkyl can have any suitable number of carbon, such asfrom 2 to 6 (C₂₋₆alkoxyalkyl), 2 to 5 (C₂₋₅alkoxyalkyl), 2 to 4(C₂₋₄alkoxyalkyl), or 2 to 3 (C₂₋₃alkoxyalkyl). Alkoxy and alkyl are asdefined above where the alkyl is divalent, and can include, but is notlimited to, methoxymethyl (CH₃OCH₂—), methoxyethyl (CH₃OCH₂CH₂—) andothers.

“Alkoxy-alkoxy” refers an alkoxy group linked to a second alkoxy groupwhich is linked to the remainder of the compound. Alkoxy is as definedabove, and can include, but is not limited to, methoxy-methoxy(CH₃OCH₂O—), methoxy-ethoxy (CH₃OCH₂CH₂O—) and others.

“Halo” or “halogen” as used herein refers to fluoro (—F), chloro (—Cl),bromo (—Br) and iodo (—I).

“Haloalkyl” as used herein refers to an alkyl as defined herein, whereinone or more hydrogen atoms of the alkyl are independently replaced by ahalo substituent, which may be the same or different. For example,C₁₋₄haloalkyl is a C₁₋₄alkyl wherein one or more of the hydrogen atomsof the C₁₋₄alkyl have been replaced by a halo substituent. Examples ofhaloalkyl groups include but are not limited to fluoromethyl,fluorochloromethyl, difluoromethyl, difluorochloromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.

“Haloalkoxy” refers to an alkoxy group where some or all of the hydrogenatoms are substituted with halogen atoms. As for an alkyl group,haloalkoxy groups can have any suitable number of carbon atoms, such asC₁₋₆. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. When all the hydrogens are replaced with a halogen, forexample by fluorine, the compounds are per-substituted, for example,perfluorinated. Haloalkoxy includes, but is not limited to,trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

“Cycloalkyl” refers to a single saturated or partially unsaturated allcarbon ring having 3 to 20 annular carbon atoms (i.e., C₃₋₂₀cycloalkyl), for example from 3 to 12 annular atoms, for example from 3to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms,or 3 to 5 annular atoms, or 3 to 4 annular atoms. The term “cycloalkyl”also includes multiple condensed, saturated and partially unsaturatedall carbon ring systems (e.g., ring systems comprising 2, 3 or 4carbocyclic rings). Accordingly, cycloalkyl includes multicycliccarbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycleshaving 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic andtetracyclic carbocycles with up to 20 annular carbon atoms). The ringsof a multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements.Non-limiting examples of monocyclic cycloalkyl include cyclopropyl,cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and1-cyclohex-3-enyl.

“Alkyl-cycloalkyl” refers to a radical having an alkyl component and acycloalkyl component, where the alkyl component links the cycloalkylcomponent to the point of attachment. The alkyl component is as definedabove, except that the alkyl component is at least divalent, analkylene, to link to the cycloalkyl component and to the point ofattachment. In some instances, the alkyl component can be absent. Thealkyl component can include any number of carbons, such as C₁₋₆, C₁₋₂,C₁₋₃, C₁₋₄, C₁₋₅, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆and C₅₋₆. The cycloalkyl component is as defined within. Exemplaryalkyl-cycloalkyl groups include, but are not limited to,methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl andmethyl-cyclohexyl.

“Heterocyclyl” or “heterocycle” or “heterocycloalkyl” as used hereinrefers to a single saturated or partially unsaturated non-aromatic ringor a multiple ring system having at least one heteroatom in the ring(i.e., at least one annular heteroatom selected from oxygen, nitrogen,and sulfur) wherein the multiple ring system includes at leastnon-aromatic ring containing at least one heteroatom. The multiple ringsystem can also include other aromatic rings and non-aromatic rings.Unless otherwise specified, a heterocyclyl group has from 3 to 20annular atoms, for example from 3 to 12 annular atoms, for example from3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms,or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annularatoms. Thus, the term includes single saturated or partially unsaturatedrings (e.g., 3, 4, 5, 6 or 7-membered rings) having from 1 to 6 annularcarbon atoms and from 1 to 3 annular heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur in the ring. The heteroatomscan optionally be oxidized to form —N(—OH)—, ═N(—O—)—, —S(═O)— or—S(═O)₂—. The rings of the multiple condensed ring (e.g. bicyclicheterocyclyl) system can be connected to each other via fused, spiro andbridged bonds when allowed by valency requirements. Heterocyclesinclude, but are not limited to, azetidine, aziridine, imidazolidine,morpholine, oxirane (epoxide), oxetane, thietane, piperazine,piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone,tetrahydrofuran, tetrahydrothiophene, dihydropyridine,tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl,6-oxa-1-azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl,2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexan-2-yl,3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl,2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl,5-azaspiro[2.4]heptanyl, pyrazolidin-3-one, piperazin-2-one,oxazolidin-2-one, and the like.

Heterocycloalkyl rings also include 9 to 15 membered fused ringheterocycloalkyls having 2, 3, or more rings wherein at least one ringis an aryl ring and at least one ring is a non-aromatic ring containingat least one heteroatom. Representative fused bicyclic heterocycloalkylsinclude, but are not limited to, indoline (dihydroindole), isoindoline(dihydroisoindole), indazoline (dihydroindazole), benzo[d]imidazole,dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran,dihydroisobenzofuran, benzo[d][1,3]dioxol, dihydrobenzo[b]dioxine,dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene,dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole,dihydrobenzo[c]isothiazole, spiro[cyclobutane-1,3′-indolin]-2′-one,spiro[cyclopropane-1,3′-indolin]-2′-one,2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole, benzo[d][1,3]dioxole,and benzo[b][1,4]thiazine, as shown in the structures below:

Fused bicyclic heterocycloalkyls can also be represented by thefollowing structures:

wherein X¹, X², X³ and X⁴ are each independently absent, —CH₂—, —NH—,—O— or —S—, at least one of X¹, X², X³ and X⁴ is —NH—, —O— or —S—, andthe dashed circle represents a saturated or partially unsaturatednon-aromatic ring. The fused bicyclic heterocycloalkyls are optionallysubstituted.

“Alkyl-heterocycloalkyl” refers to a radical having an alkyl componentand a heterocycloalkyl component, where the alkyl component links theheterocycloalkyl component to the point of attachment. The alkylcomponent is as defined above, except that the alkyl component is atleast divalent, an alkylene, to link to the heterocycloalkyl componentand to the point of attachment. The alkyl component can include anynumber of carbons, such as C₀₋₆, C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₂₋₃,C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ and C₅₋₆. In someinstances, the alkyl component can be absent. The heterocycloalkylcomponent is as defined above. Alkyl-heterocycloalkyl groups can besubstituted or unsubstituted.

“Aryl” as used herein refers to a single all carbon aromatic ring or amultiple condensed all carbon ring system wherein at least one of therings is aromatic. For example, in some embodiments, an aryl group has 6to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Arylincludes a phenyl radical. Aryl also includes multiple condensed ringsystems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20carbon atoms in which at least one ring is aromatic and wherein theother rings may be aromatic or not aromatic (i.e., carbocycle). Suchmultiple condensed ring systems are optionally substituted with one ormore (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of themultiple condensed ring system. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is also to be understood thatwhen reference is made to a certain atom-range membered aryl (e.g., 6-10membered aryl), the atom range is for the total ring atoms of the aryl.For example, a 6-membered aryl would include phenyl and a 10-memberedaryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limitingexamples of aryl groups include, but are not limited to, phenyl,indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and thelike.

“Alkyl-aryl” refers to a radical having an alkyl component and an arylcomponent, where the alkyl component links the aryl component to thepoint of attachment. The alkyl component is as defined above, exceptthat the alkyl component is at least divalent, an alkylene, to link tothe aryl component and to the point of attachment. The alkyl componentcan include any number of carbons, such as C₀₋₆, C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅,C₁₋₆, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ and C₅₋₆. Insome instances, the alkyl component can be absent. The aryl component isas defined above. Examples of alkyl-aryl groups include, but are notlimited to, benzyl and ethyl-benzene. Alkyl-aryl groups can besubstituted or unsubstituted.

“Heteroaryl” as used herein refers to a single aromatic ring that has atleast one atom other than carbon in the ring, wherein the atom isselected from the group consisting of oxygen, nitrogen and sulfur;“heteroaryl” also includes multiple condensed ring systems that have atleast one such aromatic ring, which multiple condensed ring systems arefurther described below. Thus, “heteroaryl” includes single aromaticrings of from 1 to 6 carbon atoms and 1-4 heteroatoms selected from thegroup consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogenatoms may also be present in an oxidized form provided the ring isaromatic. Exemplary heteroaryl ring systems include but are not limitedto pyridyl, pyrimidinyl, oxazolyl or furyl. “Heteroaryl” also includesmultiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4rings) wherein a heteroaryl group, as defined above, is condensed withone or more rings selected from heteroaryls (to form for example1,8-naphthyridinyl), heterocycles, (to form for example1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has 1-20 carbon atomsand 1-6 heteroatoms within the heteroaryl ring. Such multiple condensedring systems may be optionally substituted with one or more (e.g., 1, 2,3 or 4) oxo groups on the carbocycle or heterocycle portions of thecondensed ring. The rings of the multiple condensed ring system can beconnected to each other via fused, spiro and bridged bonds when allowedby valency requirements. It is to be understood that the individualrings of the multiple condensed ring system may be connected in anyorder relative to one another. It is to be understood that the point ofattachment for a heteroaryl or heteroaryl multiple condensed ring systemcan be at any suitable atom of the heteroaryl or heteroaryl multiplecondensed ring system including a carbon atom and a heteroatom (e.g., anitrogen). It also to be understood that when a reference is made to acertain atom-range membered heteroaryl (e.g., a 5 to 10 memberedheteroaryl), the atom range is for the total ring atoms of theheteroaryl and includes carbon atoms and heteroatoms. For example, a5-membered heteroaryl would include a thiazolyl and a 10-memberedheteroaryl would include a quinolinyl. Exemplary heteroaryls include butare not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl,pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl,isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl,quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl,benzimidazolyl, thionaphthenyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl-4(3H)-one, pyridin-2(1H)-one, isoquinolin-1(2H)-one, andtriazolyl.

“Alkyl-heteroaryl” refers to a radical having an alkyl component and aheteroaryl component, where the alkyl component links the heteroarylcomponent to the point of attachment. The alkyl component is as definedabove, except that the alkyl component is at least divalent, analkylene, to link to the heteroaryl component and to the point ofattachment. The alkyl component can include any number of carbons, suchas C₀₋₆, C₁₋₂, C₁₋₃, C₁₋₄, C₁₋₅, C₁₋₆, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄,C₃₋₅, C₃₋₆, C₄₋₅, C₄₋₆ and C₅₋₆. In some instances, the alkyl componentcan be absent. The heteroaryl component is as defined within.Alkyl-heteroaryl groups can be substituted or unsubstituted.

A “compound of the present disclosure” includes compounds disclosedherein, for example a compound of the present disclosure includescompounds of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e),(II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or (III-d), includingthe compounds of the Examples.

“Composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product, which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and deleterious to the recipient thereof.

“Pharmaceutically effective amount” refers to an amount of a compound ofthe present disclosure in a formulation or combination thereof, thatprovides the desired therapeutic or pharmaceutical result.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Treatment” or “treat” or “treating” as used herein refers to anapproach for obtaining beneficial or desired results. For purposes ofthe present disclosure, beneficial or desired results include, but arenot limited to, alleviation of a symptom and/or diminishment of theextent of a symptom and/or preventing a worsening of a symptomassociated with a disease or condition. In one embodiment, “treatment”or “treating” includes one or more of the following: a) inhibiting thedisease or condition (e.g., decreasing one or more symptoms resultingfrom the disease or condition, and/or diminishing the extent of thedisease or condition); b) slowing or arresting the development of one ormore symptoms associated with the disease or condition (e.g.,stabilizing the disease or condition, delaying the worsening orprogression of the disease or condition); and c) relieving the diseaseor condition, e.g., causing the regression of clinical symptoms,ameliorating the disease state, delaying the progression of the disease,increasing the quality of life, and/or prolonging survival.

“Therapeutically effective amount” or “effective amount” as used hereinrefers to an amount that is effective to elicit the desired biologicalor medical response, including the amount of a compound that, whenadministered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The effective amount can varydepending on the compound, the disease, and its severity and the age,weight, etc., of the subject to be treated. The effective amount caninclude a range of amounts. As is understood in the art, an effectiveamount may be in one or more doses, i.e., a single dose or multipledoses may be required to achieve the desired treatment endpoint. Aneffective amount may be considered in the context of administering oneor more therapeutic agents, and a single agent may be considered to begiven in an effective amount if, in conjunction with one or more otheragents, a desirable or beneficial result may be or is achieved. Suitabledoses of any co-administered compounds may optionally be lowered due tothe combined action (e.g., additive or synergistic effects) of thecompounds.

“Administering” refers to oral administration, administration as asuppository, topical contact, parenteral, intravenous, intraperitoneal,intramuscular, intralesional, intranasal or subcutaneous administration,intrathecal administration, or the implantation of a slow-release devicee.g., a mini-osmotic pump, to the subject. The administration can becarried out according to a schedule specifying frequency ofadministration, dose for administration, and other factors.

“Co-administration” as used herein refers to administration of unitdosages of the compounds disclosed herein before or after administrationof unit dosages of one or more additional therapeutic agents, forexample, administration of the compound disclosed herein within seconds,minutes, or hours of the administration of one or more additionaltherapeutic agents. For example, in some embodiments, a unit dose of acompound of the present disclosure is administered first, followedwithin seconds or minutes by administration of a unit dose of one ormore additional therapeutic agents. Alternatively, in other embodiments,a unit dose of one or more additional therapeutic agents is administeredfirst, followed by administration of a unit dose of a compound of thepresent disclosure within seconds or minutes. In some embodiments, aunit dose of a compound of the present disclosure is administered first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of one or more additional therapeutic agents. In otherembodiments, a unit dose of one or more additional therapeutic agents isadministered first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of a compound of the presentdisclosure. Co-administration of a compound disclosed herein with one ormore additional therapeutic agents generally refers to simultaneous orsequential administration of a compound disclosed herein and one or moreadditional therapeutic agents, such that therapeutically effectiveamounts of each agent are present in the body of the patient.

“Subject” refers to animals such as mammals, including, but not limitedto, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice and the like. In certain embodiments, the subject isa human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In embodiments,the disease is cancer (e.g. lung cancer, ovarian cancer, osteosarcoma,bladder cancer, cervical cancer, liver cancer, kidney cancer, skincancer (e.g., Merkel cell carcinoma), testicular cancer, leukemia,lymphoma, head and neck cancer, colorectal cancer, prostate cancer,pancreatic cancer, melanoma, breast cancer, neuroblastoma). The diseasemay be an autoimmune, inflammatory, cancer, infectious, metabolic,developmental, cardiovascular, liver, intestinal, endocrine,neurological, or other disease.

“Cancer” refers to all types of cancer, neoplasm or malignant tumorsfound in mammals, including leukemias, lymphomas, melanomas,neuroendocrine tumors, carcinomas and sarcomas. Exemplary cancers thatmay be treated with a compound, pharmaceutical composition, or methodprovided herein include lymphoma, sarcoma, bladder cancer, bone cancer,brain tumor, cervical cancer, colon cancer, esophageal cancer, gastriccancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer,leukemia, prostate cancer, breast cancer (e.g. triple negative, ERpositive, ER negative, chemotherapy resistant, herceptin resistant, HER2positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma,lobular carcinoma, primary, metastatic), ovarian cancer, pancreaticcancer, liver cancer (e.g. hepatocellular carcinoma), lung cancer (e.g.non-small cell lung carcinoma, squamous cell lung carcinoma,adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma,carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostatecancer, castration-resistant prostate cancer, breast cancer, triplenegative breast cancer, glioblastoma, ovarian cancer, lung cancer,squamous cell carcinoma (e.g., head, neck, or esophagus), colorectalcancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, ormultiple myeloma.

Additional examples include, cancer of the thyroid, endocrine system,brain, breast, cervix, colon, head & neck, esophagus, liver, kidney,lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma,stomach, uterus or Medulloblastoma, Hodgkin's Disease, Non-Hodgkin'sLymphoma, multiple myeloma, neuroblastoma, glioma, glioblastomamultiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis,primary macroglobulinemia, primary brain tumors, cancer, malignantpancreatic insulanoma, malignant carcinoid, urinary bladder cancer,premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer,neuroblastoma, esophageal cancer, genitourinary tract cancer, malignanthypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms ofthe endocrine or exocrine pancreas, medullary thyroid cancer, medullarythyroid carcinoma, melanoma, colorectal cancer, papillary thyroidcancer, hepatocellular carcinoma, Paget's Disease of the Nipple,Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma, cancer of thepancreatic stellate cells, cancer of the hepatic stellate cells, orprostate cancer.

“Leukemia” refers broadly to progressive, malignant diseases of theblood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compound,pharmaceutical composition, or method provided herein include, forexample, acute nonlymphocytic leukemia, chronic lymphocytic leukemia,acute granulocytic leukemia, chronic granulocytic leukemia, acutepromyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, aleukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovineleukemia, chronic myelocytic leukemia, leukemia cutis, embryonalleukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia,hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia,stem cell leukemia, acute monocytic leukemia, leukopenic leukemia,lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia,lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia,mast cell leukemia, megakaryocyte leukemia, micromyeloblastic leukemia,monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloidgranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacell leukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

“Sarcoma” generally refers to a tumor which is made up of a substancelike the embryonic connective tissue and is generally composed ofclosely packed cells embedded in a fibrillar or homogeneous substance.Sarcomas that may be treated with a compound, pharmaceuticalcomposition, or method provided herein include a chondrosarcoma,fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma,Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft partsarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma,chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrialsarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblasticsarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma,idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcomaof B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen'ssarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma,leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma,reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovialsarcoma, or telangiectaltic sarcoma.

“Melanoma” is taken to mean a tumor arising from the melanocytic systemof the skin and other organs. Melanomas that may be treated with acompound, pharmaceutical composition, or method provided herein include,for example, acral-lentiginous melanoma, amelanotic melanoma, benignjuvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passeymelanoma, juvenile melanoma, lentigo maligna melanoma, malignantmelanoma, nodular melanoma, subungal melanoma, or superficial spreadingmelanoma.

“Carcinoma” refers to a malignant new growth made up of epithelial cellstending to infiltrate the surrounding tissues and give rise tometastases. Exemplary carcinomas that may be treated with a compound,pharmaceutical composition, or method provided herein include, forexample, medullary thyroid carcinoma, familial medullary thyroidcarcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma,adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenalcortex, alveolar carcinoma, alveolar cell carcinoma, basal cellcarcinoma, carcinoma basocellulare, basal oid carcinoma, basosquamouscell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,bronchogenic carcinoma, cerebriform carcinoma, cholangiocellularcarcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma,corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinomacutaneum, cylindrical carcinoma, cylindrical cell carcinoma, ductcarcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma,encephaloid carcinoma, epiermoid carcinoma, carcinoma epithelialeadenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum,gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma,carcinoma gigantocellulare, glandular carcinoma, granulosa cellcarcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellularcarcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroidcarcinoma, infantile embryonal carcinoma, carcinoma in situ,intraepidermal carcinoma, intraepithelial carcinoma, Krompecher'scarcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticularcarcinoma, carcinoma lenticulare, lipomatous carcinoma, lobularcarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or carcinomavillosum.

“Metastasis,” “metastatic,” and “metastatic cancer” can be usedinterchangeably and refer to the spread of a proliferative disease ordisorder, e.g., cancer, from one organ or another non-adjacent organ orbody part. Cancer occurs at an originating site, e.g., breast, whichsite is referred to as a primary tumor, e.g., primary breast cancer.Some cancer cells in the primary tumor or originating site acquire theability to penetrate and infiltrate surrounding normal tissue in thelocal area and/or the ability to penetrate the walls of the lymphaticsystem or vascular system circulating through the system to other sitesand tissues in the body. A second clinically detectable tumor formedfrom cancer cells of a primary tumor is referred to as a metastatic orsecondary tumor. When cancer cells metastasize, the metastatic tumor andits cells are presumed to be similar to those of the original tumor.Thus, if lung cancer metastasizes to the breast, the secondary tumor atthe site of the breast consists of abnormal lung cells and not abnormalbreast cells. The secondary tumor in the breast is referred to ametastatic lung cancer. Thus, the phrase metastatic cancer refers to adisease in which a subject has or had a primary tumor and has one ormore secondary tumors. The phrases non-metastatic cancer or subjectswith cancer that is not metastatic refers to diseases in which subjectshave a primary tumor but not one or more secondary tumors. For example,metastatic lung cancer refers to a disease in a subject with or with ahistory of a primary lung tumor and with one or more secondary tumors ata second location or multiple locations, e.g., in the breast.

“Associated” or “associated with” in the context of a substance orsubstance activity or function associated with a disease (e.g.,diabetes, cancer (e.g. prostate cancer, renal cancer, metastatic cancer,melanoma, castration-resistant prostate cancer, breast cancer, triplenegative breast cancer, glioblastoma, ovarian cancer, lung cancer,squamous cell carcinoma (e.g., head, neck, or esophagus), colorectalcancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, ormultiple myeloma)) means that the disease (e.g. lung cancer, ovariancancer, osteosarcoma, bladder cancer, cervical cancer, liver cancer,kidney cancer, skin cancer (e.g., Merkel cell carcinoma), testicularcancer, leukemia, lymphoma, head and neck cancer, colorectal cancer,prostate cancer, pancreatic cancer, melanoma, breast cancer,neuroblastoma) is caused by (in whole or in part), or a symptom of thedisease is caused by (in whole or in part) the substance or substanceactivity or function.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The compounds of described herein may be prepared and/or formulated aspharmaceutically acceptable salts or when appropriate as a free base.Pharmaceutically acceptable salts are non-toxic salts of a free baseform of a compound that possesses the desired pharmacological activityof the free base. These salts may be derived from inorganic or organicacids or bases. For example, a compound that contains a basic nitrogenmay be prepared as a pharmaceutically acceptable salt by contacting thecompound with an inorganic or organic acid. Non-limiting examples ofpharmaceutically acceptable salts include sulfates, pyrosulfates,bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates,dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,bromides, iodides, acetates, propionates, decanoates, caprylates,acrylates, formates, isobutyrates, caproates, heptanoates, propiolates,oxalates, malonates, succinates, suberates, sebacates, fumarates,maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,methoxybenzoates, phthalates, sulfonates, methylsulfonates,propylsulfonates, besylates, xylenesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, and mandelates. Lists of other suitable pharmaceuticallyacceptable salts are found in Remington: The Science and Practice ofPharmacy, 21^(st) Edition, Lippincott Wiliams and Wilkins, Philadelphia,Pa., 2006.

Examples of “pharmaceutically acceptable salts” of the compoundsdisclosed herein also include salts derived from an appropriate base,such as an alkali metal (for example, sodium, potassium), an alkalineearth metal (for example, magnesium), ammonium and NX₄ ⁺ (wherein X isC₁-C₄alkyl). Also included are base addition salts, such as sodium orpotassium salts.

Provided are also compounds described herein or pharmaceuticallyacceptable salts, isomers, or a mixture thereof, in which from 1 to nhydrogen atoms attached to a carbon atom may be replaced by a deuteriumatom or D, in which n is the number of hydrogen atoms in the molecule.As known in the art, the deuterium atom is a non-radioactive isotope ofthe hydrogen atom. Such compounds may increase resistance to metabolism,and thus may be useful for increasing the half-life of the compoundsdescribed herein or pharmaceutically acceptable salts, isomer, or amixture thereof when administered to a mammal. See, e.g., Foster,“Deuterium Isotope Effects in Studies of Drug Metabolism”, TrendsPharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized bymeans well known in the art, for example by employing starting materialsin which one or more hydrogen atoms have been replaced by deuterium.

Examples of isotopes that can be incorporated into the disclosedcompounds also include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. Substitution with positron emitting isotopes, such as ¹¹C¹⁸F ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET)studies for examining substrate receptor occupancy. Isotopically-labeledcompounds of Formula (I), can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

The compounds of the embodiments disclosed herein, or theirpharmaceutically acceptable salts may contain one or more asymmetriccenters and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.The present disclosure is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optically active (+) and(−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques,for example, chromatography and fractional crystallization. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Wherecompounds are represented in their chiral form, it is understood thatthe embodiment encompasses, but is not limited to, the specificdiastereomerically or enantiomerically enriched form. Where chirality isnot specified but is present, it is understood that the embodiment isdirected to either the specific diastereomerically or enantiomericallyenriched form; or a racemic or scalemic mixture of such compound(s). Asused herein, “scalemic mixture” is a mixture of stereoisomers at a ratioother than 1:1.

“Racemates” refers to a mixture of enantiomers. The mixture can compriseequal or unequal amounts of each enantiomer.

“Stereoisomer” and “stereoisomers” refer to compounds that differ in thechirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers. The compounds may exist in stereoisomericform if they possess one or more asymmetric centers or a double bondwith asymmetric substitution and, therefore, can be produced asindividual stereoisomers or as mixtures. Unless otherwise indicated, thedescription is intended to include individual stereoisomers as well asmixtures. The methods for the determination of stereochemistry and theseparation of stereoisomers are well-known in the art (see, e.g.,Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wileyand Sons, New York, 1992).

“Tautomer” refers to alternate forms of a compound that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a ring atomattached to both a ring —NH— and a ring ═N— such as pyrazoles,imidazoles, benzimidazoles, triazoles, and tetrazoles.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. A dash at the front or end of a chemical group is a matter ofconvenience; chemical groups may be depicted with or without one or moredashes without losing their ordinary meaning. A wavy line drawn througha line in a structure indicates a point of attachment of a group. Adashed line indicates an optional bond. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or the point at which it isattached to the remainder of the molecule. For instance, the group“—SO₂CH₂—” is equivalent to “—CH₂SO₂—” and both may be connected ineither direction. Similarly, an “arylalkyl” group, for example, may beattached to the remainder of the molecule at either an aryl or an alkylportion of the group. A prefix such as “C_(u-v)” or (C_(u)-C_(v))indicates that the following group has from u to v carbon atoms. Forexample, “C₁₋₆alkyl” and “C₁-C₆alkyl” both indicate that the alkyl grouphas from 1 to 6 carbon atoms.

“Solvate” as used herein refers to the result of the interaction of asolvent and a compound. Solvates of salts of the compounds describedherein are also provided. Hydrates of the compounds described herein arealso provided.

“Prodrug” as used herein refers to a derivative of a drug that uponadministration to the human body is converted to the parent drugaccording to some chemical or enzymatic pathway.

II. Compounds

The present disclosure provides compounds that are inhibitors of CD73.In some embodiments, the disclosure provides compounds of Formula (I) asdescribed herein, and/or pharmaceutically acceptable salt(s) thereof. Insome embodiments, a compound is provided having the structure of Formula(I),

and/or pharmaceutically acceptable salt(s) thereof. Some embodimentsprovide a compound having the structure of Formula (I).

In some embodiments, the compound of Formula (I) is

or a pharmaceutically acceptable salt thereof, wherein

-   -   Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —C₁₋₆alkyl-O—C₁₋₆alkyl,        —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-O—, —C₃₋₇cycloalkyl-O—,        —O—C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl-C₁₋₃alkyl, —S(═O)₂—,        —S(═O)₂CH₂—, —CH₂S(═O)₂—, —N(R^(a))—, —N(R^(a))CH₂—,        —C₁₋₆alkyl-N(R^(b))—, —C₃₋₇cycloalkyl-N(R^(b))—,        —N(R^(a))C(═O)—, —C₁₋₃alkylN(R^(a))C(═O)—,        heterocycloalkyl-C(═O)—, heterocycloalkyl-N(H)C(═O)—,        heterocycloalkyl, heterocycloalkyl-C₁₋₆alkyl-O—, or        heterocycloalkyl-O—, wherein each alkyl, cycloalkyl, or        heterocycloalkyl is optionally substituted with one to four        halogens and is further optionally substituted with one or two        groups independently selected from —CN, —C₁₋₃alkyl and        —C₁₋₃haloalkyl;    -   one or two of Z¹, Z² and Z³ is CR² and the remaining one or two        of Z¹, Z², and Z³ is N;    -   one of W¹ and W² is N and the other is C;    -   R¹ is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl,        —C₁₋₆alkyl-C₆₋₁₂aryl, —C₁₋₆alkyl-heteroaryl, heterocycloalkyl,        heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl,        cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally        substituted with one to three halogens and is further optionally        substituted with one or two R³;    -   R² is each independently hydrogen, halogen, —CN, —C₁₋₆alkyl,        —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),        —C(═O)heterocycloalkyl, —C(═O)N(R^(b))C₆₋₁₂aryl,        —C(═O)N(R^(b))heteroaryl, —C(═O)N(R^(b))(R^(b)),        —C₁₋₆alkyl-S(═O)₂C₆₋₁₂aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl,        heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl is optionally substituted        with one to three halogens and is further optionally substituted        with one to three R⁴;    -   R³ is halogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl,        —C₁₋₃alkyl-C₃₋₇cycloalkyl, —C₁₋₃alkyl-heterocycloalkyl,        —N(R^(b))(R^(b)), —N(H)C(═O)O—R^(c), —C(═O)N(R^(b))(R^(b)),        —C(═O)OC₁₋₆alkyl, —C(═O)OC₁₋₆alkylC₆₋₁₂aryl, —C(═O)C₁₋₃alkyl,        —C(═O)C₃₋₇cycloalkyl, —C(═O)heterocycloalkyl,        —OC(═O)heterocycloalkyl, —OC(═O)N(H)C₁₋₆alkyl,        —OC(═O)N(H)C₃₋₇cycloalkyl, —OC(═O)OC₁₋₆alkyl,        —OC(═O)N(H)C₆₋₁₂aryl, or —OR′, wherein each alkyl, cycloalkyl,        heterocycloalkyl, or aryl is optionally substituted with one to        three halogens and is further optionally substituted with one or        two 12′;    -   R⁴ is halogen, —CN, —OR′, —C₁₋₆alkyl, —N(R^(b))(R^(b)), or        —C₁₋₆haloalkyl;    -   R^(a) is each independently hydrogen, or —C₁₋₃alkyl;    -   R^(b) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₁₋₆alkyl-C₃₋₇cycloalkyl,        —C₃₋₇cycloalkyl-C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —C₃₋₇halocycloalkyl, or —C(═O)C₁₋₆alkyl; and    -   R^(c) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl, —C₁₋₃alkyl-C₃₋₇cycloalkyl,        —C₁₋₃alkyl-C₃₋₇cyclohaloalkyl, —OC₁₋₆alkyl, or        —C₃₋₇halocycloalkyl; and    -   wherein each heterocycloalkyl or heteroaryl bears one to four        heteroatoms each independently selected from N, O, and S;    -   wherein each heterocycloalkyl has 4 to 15 ring members; and    -   wherein each heteroaryl has 5 to 15 ring members.

In some embodiments, the compound of Formula (I) is

and/or a pharmaceutically acceptable salt thereof, wherein

-   -   Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —C₁₋₆alkyl-O—C₁₋₆alkyl,        —O—C₁₋₆alkyl, —C₃₋₇cycloalkyl-O—, —O—C₃₋₇cycloalkyl,        —C₃₋₇cycloalkyl-C₁₋₃alkyl-, —S(═O)₂—, —S(═O)₂CH₂—, —CH₂S(═O)₂—,        —N(R^(a))—, —N(R^(a))CH₂—, —C₁₋₆alkyl-N(R^(b))—,        —C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—,        C₁₋₃alkylN(R^(a))C(═O)—, heterocycloalkyl-C(═O)—,        heterocycloalkyl or heterocycloalkyl-O—, wherein each alkyl,        cycloalkyl, or heterocycloalkyl is optionally substituted with        one to four halogens and is further optionally substituted with        one or two groups independently selected from —CN and        —C₁₋₃alkyl;    -   one or two of Z¹, Z² and Z³ is CR² and the remaining one or two        of Z¹, Z², and Z³ is N;    -   one of W¹ and W² is N and the other is C;    -   R¹ is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl,        heterocycloalkyl, heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein        each alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is        optionally substituted with one to three halogens and is further        optionally substituted with one or two R³;    -   R² is each independently hydrogen, halogen, —CN, —C₁₋₆alkyl,        —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),        —C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))heteroaryl,        —C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl,        —N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl,        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl is optionally substituted with one to three halogens        and is further optionally substituted with one to three R⁴;    -   R³ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —N(R^(b))(R^(b)), —C(═O)OC₁₋₆alkyl, —OC(═O)N(H)C₁₋₆alkyl,        —OC(═O)OC₁₋₆alkyl, or —OR′;    -   R⁴ is halogen, —CN, —OR′, —C₁₋₆alkyl, —N(R^(b))(R^(b)), or        —C₁₋₆haloalkyl;    -   R^(a) is each independently hydrogen, or —C₁₋₃alkyl;    -   R^(b) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl,        —C₃₋₇halocycloalkyl, or —C(═O)C₁₋₆alkyl; and    -   R^(c) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl, or —C₃₋₇halocycloalkyl; and    -   wherein each heterocycloalkyl or heteroaryl bears one to four        heteroatoms each independently selected from N, O, and S;    -   wherein each heterocycloalkyl has 4 to 10 ring members; and    -   wherein each heteroaryl has 5 to 10 ring members.

In some embodiments, the disclosure provides a compound having thestructure of Formula (I), and/or a pharmaceutically acceptable saltthereof, wherein

-   -   Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —O—C₁₋₆alkyl,        —C₃₋₇cycloalkyl-O—, —O—C₃₋₇cycloalkyl,        —C₃₋₇cycloalkyl-C₁₋₃alkyl-, —S(═O)₂—, —S(═O)₂CH₂—, —CH₂S(═O)₂—,        —N(R^(a))—, —N(R^(a))CH₂—, —C₁₋₆alkyl-N(R^(b))—,        —C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—,        —C₁₋₃alkylN(R^(a))C(═O)—, heterocycloalkyl-C(═O)—,        —O—C₁₋₆alkyl-O—, heterocycloalkyl-N(H)C(═O)—,        heterocycloalkyl-C₁₋₆alkyl-O—, or heterocycloalkyl, wherein each        alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted        with one to four halogens and is further optionally substituted        with one or two groups independently selected from —CN—C₁₋₃alkyl        and —C₁₋₃haloalkyl;    -   R¹ is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl,        —C₁₋₆alkyl-C₆₋₁₂aryl, —C₁₋₆alkyl-heteroaryl, heterocycloalkyl,        heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl,        cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally        substituted with one to three halogens and is further optionally        substituted with one or two R³;    -   R³ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —C₁₋₃alkyl-C₃₋₇cycloalkyl, —C₁₋₃alkyl-heterocycloalkyl,        —N(R^(b))(R^(b)), —N(H)C(═O)O—R^(c), —C(═O)N(R^(b))(R^(b)),        —C(═O)OC₁₋₆alkylC₆₋₁₂aryl, —C(═O)C₁₋₃alkyl,        —C(═O)C₃₋₇cycloalkyl, —C(═O)heterocycloalkyl,        —OC(═O)heterocycloalkyl, —OC(═O)N(H)C₃₋₇cycloalkyl,        —OC(═O)N(H)C₆₋₁₂aryl, or —OR′;    -   R^(b) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl, —C₃₋₇halocycloalkyl, or        —C(═O)C₁₋₆alkyl; and        wherein Z¹, Z², Z³, W¹, W², R², R⁴, R^(a), and R^(c) are as        described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (I), and/or a pharmaceutically acceptable saltthereof, wherein

-   -   Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —O—C₁₋₆alkyl,        —C₃₋₇cycloalkyl-O—, —O—C₃₋₇cycloalkyl,        —C₃₋₇cycloalkyl-C₁₋₃alkyl-, —S(═O)₂—, —S(═O)₂CH₂—, —CH₂S(═O)₂—,        —N(R^(a))—, —N(R^(a))CH₂—, —C₁₋₆alkyl-N(R^(b))—,        —C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—,        —C₁₋₃alkylN(R^(a))C(═O)—, heterocycloalkyl-C(═O)—, or        heterocycloalkyl, wherein each alkyl, cycloalkyl, or        heterocycloalkyl is optionally substituted with one to four        halogens and is further optionally substituted with one or two        groups independently selected from —CN and —C₁₋₃alkyl;    -   R¹ is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆aryl,        heterocycloalkyl, heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein        each alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is        optionally substituted with one to three halogens and is further        optionally substituted with one or two R³;    -   R³ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —N(R^(b))(R^(b)), or —OR′;    -   R^(b) is each independently hydrogen, —C₁₋₆alkyl,        —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl, —C₃₋₇halocycloalkyl, or        —C(═O)C₁₋₆alkyl; and        wherein Z¹, Z², Z³, W¹, W², R², R⁴, R^(a), and R^(c) are as        described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-a):

and/or pharmaceutically acceptable salt(s) thereof, wherein Y, R¹,R^(2a), and R^(2b), are as described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-a):

-   -   wherein R^(2a) and R^(2b) are each independently hydrogen,        halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀cycloalkyl, —O—C₁₋₆alkyl,        —C(═O)OR^(a), —C(═O)heterocycloalkyl, —C(═O)N(R^(b))C₆₋₁₂aryl,        —C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆₋₁₂aryl,        —N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl,        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl is optionally substituted with one to three halogens        and is further optionally substituted with one to three R⁴,    -   and wherein R¹ and Y are as described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-a):

and/or pharmaceutically acceptable salt(s) thereof,

-   -   wherein R^(2a) and R^(2b) are each independently hydrogen,        halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀cycloalkyl, —O—C₁₋₆alkyl,        —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))(R^(b)),        —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl,        heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl is optionally substituted        with one to three halogens and is further optionally substituted        with one to three R⁴, and wherein R¹ and Y are as described        herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-b):

and/or pharmaceutically acceptable salt(s) thereof, wherein Y, R¹, andR^(2b), are as described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-b):

and/or pharmaceutically acceptable salt(s) thereof,

-   -   wherein R^(2b) is hydrogen, halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀        cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl,        —C(═O)N(R^(b))heteroaryl, —C(═O)N(R^(b))(R^(b)),        —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl,        heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl is optionally substituted        with one to three halogens and is further optionally substituted        with one to three R⁴, and wherein R¹ and Y are as described        herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-c):

and/or pharmaceutically acceptable salt(s) thereof, wherein Y, R¹,R^(2a), and R^(2b), are as described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-c):

and/or pharmaceutically acceptable salt(s) thereof,

-   -   wherein R^(2a) and R^(2b) are each independently hydrogen,        halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀cycloalkyl, —O—C₁₋₆alkyl,        —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))(R^(b)),        —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl,        heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl is optionally substituted        with one to three halogens and is further optionally substituted        with one to three R⁴, and wherein R¹ and Y are as described        herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-d):

and/or pharmaceutically acceptable salt(s) thereof, wherein Y, R¹, andR^(2a) are as described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-d):

and/or pharmaceutically acceptable salt(s) thereof,

-   -   wherein R^(2a) is hydrogen, halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀        cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl,        —C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl,        —N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl,        wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, or        heteroaryl is optionally substituted with one to three halogens        and is further optionally substituted with one to three R⁴,    -   and wherein R¹ and Y are as described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-e):

and/or pharmaceutically acceptable salt(s) thereof, wherein Y, R¹, and Re a, are as described herein.

In some embodiments, the disclosure provides a compound having thestructure of Formula (II-e):

and/or pharmaceutically acceptable salt(s) thereof,

-   -   wherein R^(2a) is independently hydrogen, halogen, —CN,        —C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),        —C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))(R^(b)),        —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl,        heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl is optionally substituted        with one to three halogens and is further optionally substituted        with one to three R⁴,    -   and wherein R¹ and Y are as described herein.

Some embodiments provide a compound having the structure of Formula(II-a), (II-b), (II-c), (II-d), or (II-e), wherein R¹ is optionallysubstituted with one or two R³; and wherein R^(2a) and R^(2b) are eachindependently hydrogen, halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl,—O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl,—C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)),—C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with one to three halogens and is further optionallysubstituted with one to three R⁴.

In some embodiments, a compound of the disclosure is a compound whereinR¹ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl, heterocycloalkyl,heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl,aryl, or heteroaryl is optionally substituted with one to three halogensand is further optionally substituted with one or two R³. In someembodiments, a compound of the disclosure is a compound wherein R¹ is—C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl, heterocycloalkyl, heteroaryl,or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl, aryl, orheteroaryl is optionally substituted with one to four halogens.

In some embodiments, a compound of the disclosure is a compound whereinR¹ is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆aryl, heterocycloalkyl,heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl,aryl, or heteroaryl is optionally substituted with one to three halogensand is further optionally substituted with one or two R³. In someembodiments, a compound of the disclosure is a compound wherein R¹ is—C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆aryl, heterocycloalkyl, heteroaryl, or—C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl, aryl, orheteroaryl is optionally substituted with one to four halogens.

In some embodiments, a compound of the disclosure is a compound whereinR¹ is isopropyl, —F, —CF₃, pyrrolidinyl, morpholinyl, imidazolyl,phenyl, pyridinyl, —CH₂OCH₃, —C(CH₃)₃ or cyclopropyl, each of which isoptionally substituted, to the extent valency permits, with one to threehalogens and is further optionally substituted with one or two R³. Insome embodiments, a compound of the disclosure is a compound, orpharmaceutically acceptable salt thereof, wherein R¹ is isopropyl, —F,—CF₃, pyrrolidinyl, morpholinyl, imidazolyl, phenyl, pyridinyl,—CH₂OCH₃, —C(CH₃)₃ or cyclopropyl, each of which is optionallysubstituted, to the extent valency permits, with one to three halogens.In some embodiments, a compound of the disclosure is a compound, orpharmaceutically acceptable salt thereof, wherein R¹ is isopropyl, —F,—CF₃, pyrrolidinyl, morpholinyl, imidazolyl, phenyl, pyridinyl,—CH₂OCH₃, —C(CH₃)₃ or cyclopropyl.

In some embodiments, a compound of the disclosure is a compound whereinR¹ is:

In some embodiments, a compound of the disclosure is a compound whereinR¹ is:

In some embodiments, a compound of the disclosure is a compound whereinR² is selected from hydrogen, halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl,—C(═O)N(R^(b))heteroaryl, —C(═O)N(R^(b))(R^(b)),—C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl,or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl is optionally substituted with one to three halogens andis further optionally substituted with one to three R⁴.

In some embodiments, a compound of the disclosure is a compound whereinR^(2a) and R^(2b) are each selected from hydrogen, halogen, —CN,—C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),—C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))heteroaryl,—C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)),—C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with one to three halogens and is further optionallysubstituted with one to three R⁴.

In some embodiments, a compound of the disclosure is a compound whereinR², R^(2a) and R^(2b) are each independently hydrogen, halogen,—C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl, —C(═O)OR^(a), —C₁₋₆alkyl-S(═O)₂C₆aryl,heteroaryl or —C₆aryl, wherein each alkyl, cycloalkyl, heteroaryl oraryl is optionally substituted with one to three halogens and is furtheroptionally substituted with one or two R⁴.

In some embodiments, a compound of the disclosure is a compound whereinR², R^(2a) and R^(2b) are each independently —H, —F, —CH₃, —CH₂CH₃,—CF₃, phenyl, —CH₂SO₂Ph, —C(═O)OCH₂CH₃, cyclopropyl, or

In some embodiments, a compound of the disclosure is a compound whereinR², R^(2a), or R^(2b) is:

In some embodiments, a compound of the disclosure is a compound whereinR², R^(2a), or R^(2b) is:

In some embodiments, a compound of the disclosure is a compound whereinR², R^(2a), or R^(2b) is:

In some embodiments, a compound of the disclosure is a compound whereinR³ is —CH₃, —CH₂CH₃, —F, —Cl, —CF₃, cyclopropyl, —OCF₃ or —CN.

In some embodiments, a compound of the disclosure is a compound whereinR³ is —O—CH₃ or

In some embodiments, a compound of the disclosure is a compound whereinR⁴ is —F or —CF₃.

In some embodiments, a compound of the disclosure is a compound whereinY is a bond.

In some embodiments, a compound of the disclosure is a compound whereinY is:

In some embodiments, a compound of the disclosure is a compound Y—R¹ is:—CH₃, —CH₂CH₃, isopropyl, —O-isopropyl, —OPh,

each of which is optionally substituted with one or two R³.

In some embodiments, a compound of the disclosure is a compound Y—R¹ is:

In some embodiments, a compound of the disclosure is a compound Y—R¹ is:

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-f):

or a pharmaceutically acceptable salt thereof, wherein R¹, R^(2a) andR^(2b) are as described herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-f):

or a pharmaceutically acceptable salt thereof,

-   -   wherein R¹ is phenyl or heteroaryl, each of which is optionally        substituted with one to three halogens and is further optionally        substituted with one or two R³, R^(2a) and R^(2b) are each        independently hydrogen or halogen.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-a):

or a pharmaceutically acceptable salt thereof, wherein R¹ is asdescribed herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-a):

or a pharmaceutically acceptable salt thereof,

-   -   wherein R¹ is phenyl or heteroaryl, each of which is optionally        substituted with one to three halogens and is further optionally        substituted with one or two R³.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-g):

or a pharmaceutically acceptable salt thereof, wherein R¹, R^(2a) andR^(2b) are as described herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-g):

or a pharmaceutically acceptable salt thereof,

-   -   wherein R¹ is phenyl or heteroaryl, each of which is optionally        substituted with one to three halogens and is further optionally        substituted with one or two R³, R^(2a) and R^(2b) are each        independently hydrogen or halogen.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-b):

or a pharmaceutically acceptable salt thereof, wherein R¹ is asdescribed herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-b):

or a pharmaceutically acceptable salt thereof,

-   -   wherein R¹ is phenyl or heteroaryl, each of which is optionally        substituted with one to three halogens and is further optionally        substituted with one or two R³.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-h):

or a pharmaceutically acceptable salt thereof, wherein R¹, R^(2a) andR^(2b) are as described herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-h):

or a pharmaceutically acceptable salt thereof,

-   -   wherein R¹ is C₃₋₇cycloalkyl or heterocycloalkyl, each of which        is optionally substituted with one to three halogens and is        further optionally substituted with one or two R³, R^(2a) and        R^(2b) are each independently hydrogen or halogen.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-c):

or a pharmaceutically acceptable salt thereof, wherein m, R⁵, R^(2a) andR^(2b) are as described herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-c):

wherein

-   -   each R⁵ is independently halogen, —CN, —C₁₋₆alkyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-N(R^(d))(R^(d)), —OR′,        —N(R^(b))(R^(b)), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,        —OC(═O)N(H)C₁₋₆alkyl, —OC(═O)OC₁₋₆alkyl, —O—C₆₋₁₂aryl,        —O-heteroaryl, or —C₁₋₆haloalkyl, or the two R⁵ moieties join        together to form a 3 to 6 membered cycloalkyl or        heterocycloalkyl ring, wherein the ring is optionally        substituted with one to three halogens and is further optionally        substituted with one to three R⁶;    -   R⁶ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —N(R^(b))(R^(b)), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,        —OC(═O)N(H)C₁₋₆alkyl, —OC(═O)OC₁₋₆alkyl, or —OR′; and    -   m is 0, 1, 2, 3 or 4;    -   and wherein R^(2a) and R^(2b) are as described herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-c):

or a pharmaceutically acceptable salt thereof,wherein

-   -   each R⁵ is independently halogen, —CN, —C₁₋₆alkyl,        —C₃₋₇cycloalkyl, —C₁₋₆alkyl-N(R^(d))(R^(d)), —OR′,        —N(R^(b))(R^(b)), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,        —OC(═O)N(H)C₁₋₆alkyl, —OC(═O)OC₁₋₆alkyl, or —C₁₋₆haloalkyl, or        the two R⁵ moieties join together to form a 3 to 6 membered        cycloalkyl or heterocycloalkyl ring, wherein the ring is        optionally substituted with one to three halogens and is further        optionally substituted with one to three R⁶;    -   R⁶ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,        —N(R^(b))(R^(b)), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,        —OC(═O)N(H)C₁₋₆alkyl, —OC(═O)OC₁₋₆alkyl, or —OR′; and    -   m is 0, 1, 2, 3 or 4;    -   and wherein R^(2a) and R^(2b) are as described herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-d):

-   -   or a pharmaceutically acceptable salt thereof, wherein R^(7a),        R^(7b), R^(7c), R^(7d), R^(2a) and R^(2b) are as described        herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-d):

or a pharmaceutically acceptable salt thereof,

-   -   wherein R^(7a), R^(7b), R^(7c), and R^(7d) are independently        halogen, —C₁₋₆alkyl or —C₁₋₆haloalkyl, or the two of the R^(7a),        R^(7b), R^(7c), or R^(7d) moieties join together to form a 3 to        6 membered cycloalkyl ring, wherein the ring is optionally        substituted with one to three halogens,    -   and wherein R^(2a) and R^(2b) are as described herein.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-f), (II-g), (III-a) or (III-b), or apharmaceutically acceptable salt thereof, wherein R¹ is phenyl orheteroaryl, each of which is optionally substituted with one to threehalogens. In some embodiments, a compound of the disclosure is acompound having the structure of Formula (II-f), (II-g), (III-a) or(III-b), or a pharmaceutically acceptable salt thereof, wherein R¹ isphenyl or heteroaryl, each of which is optionally substituted with oneor two R³. In some embodiments, a compound of the disclosure is acompound having the structure of Formula (II-f), (II-g), (III-a) or(III-b), wherein R¹ is phenyl or heteroaryl substituted with one or twoR³.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (II-h), or a pharmaceutically acceptable saltthereof, wherein R¹ is C₃₋₇cycloalkyl or heterocycloalkyl, each of whichis optionally substituted with one to three halogens. In someembodiments, a compound of the disclosure is a compound having thestructure of Formula (II-h), or a pharmaceutically acceptable saltthereof, wherein R¹ is C₃₋₇cycloalkyl or heterocycloalkyl, each of whichis optionally substituted with one or two R³. In some embodiments, acompound of the disclosure is a compound having the structure of Formula(II-h), wherein R¹ is C₃₋₇cycloalkyl or heterocycloalkyl substitutedwith one or two R³.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-c), or a pharmaceutically acceptable saltthereof, wherein R⁵ is independently halogen, —CN, —C₁₋₆alkyl,—C₃₋₇cycloalkyl, —C₁₋₆alkyl-N(R^(d))(R^(d)), —OR′, —N(R^(b))(R^(b)),—C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —OC(═O)N(H)C₁₋₆alkyl,—OC(═O)OC₁₋₆alkyl, —O—C₆₋₁₂aryl, —O-heteroaryl, or —C₁₋₆haloalkyl. Insome embodiments, a compound of the disclosure is a compound having thestructure of Formula (III-c), or a pharmaceutically acceptable saltthereof, wherein R⁵ is independently halogen, —C₁₋₆alkyl,—C(═O)OC₁₋₆alkyl, or —OC(═O)N(H)C₁₋₆alkyl. In some embodiments, acompound of the disclosure is a compound having the structure of Formula(III-c), or a pharmaceutically acceptable salt thereof, wherein two R⁵moieties join together to form a 3 to 6 membered cycloalkyl orheterocycloalkyl ring, wherein the ring is optionally substituted withone to three halogens and is further optionally substituted with one tothree R⁶. In some embodiments, a compound of the disclosure is acompound having the structure of Formula (III-c), wherein two R⁵moieties join together to form a 3 to 6 membered cycloalkyl orheterocycloalkyl ring.

In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-d), or a pharmaceutically acceptable saltthereof, wherein R^(7a), R^(7b), R^(7c), and R^(7d) are independentlyhalogen, —C₁₋₆alkyl or —C₁₋₆haloalkyl. In some embodiments, a compoundof the disclosure is a compound having the structure of Formula (III-d),or a pharmaceutically acceptable salt thereof, wherein R^(7a), R^(7b),R^(7c), and R^(7d) are independently halogen, —C₁₋₆alkyl or—C₁₋₆haloalkyl, and the two of the R^(7a), R^(7b), R^(7c), or R^(7d)moieties join together to form a 3 to 6 membered cycloalkyl ring,wherein the ring is optionally substituted with one to three halogens.In some embodiments, a compound of the disclosure is a compound havingthe structure of Formula (III-d), or a pharmaceutically acceptable saltthereof, wherein the two of the R^(7a), R^(7b), R^(7c), or R^(7d)moieties join together to form a 3 to 6 membered cycloalkyl orheterocycloalkyl ring.

In some embodiments, the compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d) is a compound described in Table 2, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f),(II-g), (III-a), (III-b), (III-c), or (III-d) is a compound described inTable 2.

In some embodiments, the compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d) is the compound having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d) is the compound having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d) is the compound having the structure:

In some embodiments, the compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d) is the compound having the structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d) is the compound having the structure:

or a pharmaceutically acceptable salt thereof.

Also falling within the scope herein are the in vivo metabolic productsof the compounds described herein, to the extent such products are noveland unobvious over the prior art. Such products may result for examplefrom the oxidation, reduction, hydrolysis, amidation, esterification andthe like of the administered compound, primarily due to enzymaticprocesses. Accordingly, included are novel and unobvious compoundsproduced by a process comprising contacting a compound with a mammal fora period of time sufficient to yield a metabolic product thereof. Suchproducts typically are identified by preparing a radiolabelled (e.g. ¹⁴Cor ³H) compound, administering it parenterally in a detectable dose(e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse,guinea pig, monkey, or to man, allowing sufficient time for metabolismto occur (typically about 30 seconds to about 30 hours) and isolatingits conversion products from the urine, blood or other biologicalsamples. These products are easily isolated since they are labeled(others are isolated by the use of antibodies capable of bindingepitopes surviving in the metabolite). The metabolite structures aredetermined in conventional fashion, e.g. by MS or NMR analysis. Ingeneral, analysis of metabolites is done in the same way as conventionaldrug metabolism studies well-known to those skilled in the art.

III. Methods of Preparing

The compounds of the present disclosure can be prepared by a variety ofmethods. For example, Schemes 1-4 show representative syntheses of thecompounds of the present disclosure.

Representative synthetic Scheme 1 shows a general synthesis of compoundsof the disclosure. The methodology is compatible with a wide variety offunctionalities. In Representative Synthesis 1, a suitably substitutedchloroimidazopyridazine (or the corresponding bromo- or iodo-compound)is combined with (2,4-dimethoxypyrimidin-5-yl)boronic acid in a suitablesolvent system (e.g. water+dioxane, THF, DME, toluene etc.) in thepresence of a palladium catalyst (e.g. Pd(dppf)Cl₂, Pd(PPh₃)₄ etc.) andbase (e.g. Cs₂CO₃, K₂CO₃, K₃PO₄ etc.) at elevated temperature (e.g.,ranging from about 80-120° C.), which can be performed, for example, ina microwave reactor or with conventional heating. Subsequently, theresultant suitably substituted 2,4-dimethoxypyrimidine can be treatedwith an acid (e.g hydrochloric acid) in a suitable solvent system (e.g.water+methanol, ethanol etc.) at elevated temperature (e.g., rangingfrom about 50-80° C.).

Representative synthetic Scheme 2 shows a general synthesis of thecompounds of the embodiments. The methodology is compatible with a widevariety of functionalities. In Representative synthetic Scheme 2, asuitably substituted bromoimidazopyridazine (or the correspondingchloro- or iodo-compound) is combined with an alkyl boronic acid orboronic acid derivate (e.g. boronate ester or trifluoroborate salt) in asuitable solvent system (e.g. water+dioxane, THF, DME, toluene etc.) inthe presence of a palladium catalyst (e.g. Pd(dppf)Cl₂, cataCXium-A-PdG3 etc.) and base (e.g. Cs₂CO₃, K₂CO₃, K₃PO₄ etc.) at elevatedtemperature (e.g., ranging from about 90-150° C.), which can beperformed in microwave reactor or with conventional heating).

Representative synthetic Scheme 3 shows a general synthesis of thecompounds of the embodiments. The methodology is compatible with a widevariety of functionalities. In representative synthetic Scheme 3, asuitably substituted bromoimidazopyridazine (or the correspondingchloro- or fluoro-compound) is combined with a nucleophile (e.g. amine,alcohol, heterocycle etc.) in a suitable solvent system (e.g.acetonitrile, EtOH, THF, NMP etc.) in the presence of a base (e.g.Cs₂CO₃, K₂CO₃ triethylamine, DIPEA, NaH etc.) at ambient or elevatedtemperature (e.g., ranging from about 20-90° C.).

Representative synthetic Scheme 4 shows a general synthesis of thecompounds of the embodiments. The methodology is compatible with a widevariety of functionalities. In representative synthetic Scheme 4, asuitably substituted chloroimidazopyridazine is combined with a radicalprecursor, such as a sodium or zinc alkyl sulfinate, in a suitablesolvent system (e.g. DMSO/H₂O, DCE/H₂O etc.) in the presence of anoxidant (e.g. TBHP) at ambient or elevated temperature (e.g., rangingfrom about 20-60° C.). A variety of radical precursor and reactionconditions can be used to generate the appropriate alkyl radicalintermediate, including Minisci conditions (i.e. alkyl carboxylic acid,(NH₄)₂S₂O₉, AgNO₃, TFA).

Representative synthetic Scheme 5 shows a general synthesis of thecompounds of the embodiments. The methodology is compatible with a widevariety of functionalities. In representative synthetic Scheme 5, asuitably substituted aryl or heteroaryl halide is combined withpotassium vinyltrifluoroborate (or the analogous -Bpin, -BMIDA or-B(OH)₂ reagent) in a suitable solvent system (e.g. water+THF, dioxane,DME, toluene etc.) in the presence of a palladium catalyst (e.g.Pd(dppf)Cl₂, Pd(PPh₃)₄ etc.) and base (e.g. K₂CO₃, Cs₂CO₃, K₃PO₄ etc.)at elevated temperature (e.g., ranging from about 80-120° C., can beperformed in microwave reactor or with conventional heating).Subsequently, the suitably substituted alkene, in a suitable solventsystem (e. g. DCM), is treated withtetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2-oxazolyl-N]phenyl]ruthenium(II)hexafluorophosphate (or another suitable transition metal catalyst) and1,3-dioxoisoindolin-2-yl 2-diazoacetate at low temperature (e.g.,ranging from about −20° C.-5° C.). The resulting, suitably substituted,N-hydroxyphthalimide ester is combined with methyl isonicotinate (oranother suitable isonicotinate derivative, e.g. isonicotinate t-butylester, etc.) and bis(pinacolato)diboron in a suitable solvent (e. g.EtOAc, CF₃Ph, etc. isonicotinate t-butyl ester) at elevated temperature(e.g., ranging from about 60-100° C.). Alternatively, the borylationreaction can be performed by combining a suitably substituted,N-hydroxyphthalimide ester with bis(catecholato)diboron in a suitablesolvent system (e. g. DMF) under blue LED lights, and the resultingboronate ester combined with pinacol and triethylamine.

Alternatively, this reaction sequence can provide racemic mixtures ofthe compounds by combining a suitably substituted alkene with ethyldiazoacetate in a suitable solvent system (i.e. Toluene) at elevatedtemperature (e.g. ranging from about 80-120° C.). Subsequently, theethyl ester can be hydrolyzed under basic aqueous conditions (e.g. LiOHor NaOMe), and the resulting acid can be combined withN-hydroxyphthalmide with a suitable coupling reagent (e.g. DIC, EDC).The final borylation step can be performed as above.

Pharmaceutical Formulations

In some embodiments, the present disclosure provides a pharmaceuticalformulation comprising a pharmaceutically effective amount of a compoundof the present disclosure, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or excipient. Alsoprovided herein is a pharmaceutical formulation comprising apharmaceutically effective amount of a compound of Formula (I), (II-a),(II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a),(III-b), (III-c), or (III-d), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier or excipient.

In some embodiments, the pharmaceutical composition is for use intreating a cancer.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutic agents. Any suitable additionaltherapeutic agent or combination therapy can be used with the compoundsof Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g),(II-h), (III-a), (III-b), (III-c), or (III-d), or a pharmaceuticallyacceptable salt thereof, such as the agents and therapies describedwithin.

In some embodiments, the pharmaceutical composition comprises a compoundof Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g),(II-h), (III-a), (III-b), (III-c), or (III-d), and an additionaltherapeutic agent, wherein the additional therapeutic agent is ananticancer agent. In some embodiments, the pharmaceutical composition isthe pharmaceutical composition wherein the additional therapeutic agentis independently an anti-neoplastic agent, chemotherapy, radiationtherapy, or resection therapy. In some embodiments, the pharmaceuticalcomposition is the pharmaceutical composition wherein the additionaltherapeutic agent is independently rituxan, doxorubicin, gemcitabine,nivolumab, pembrolizumab, nivolumab, pembrolizumab, atezolizumab, oripilimumab. In some embodiments, the pharmaceutical composition is thepharmaceutical composition wherein the additional therapeutic agent is aPD-1/PD-L1 inhibitor.

In some embodiments, the pharmaceutical composition is thepharmaceutical composition wherein the additional therapeutic agentcomprises one or more populations of immune cells, such as naturalkiller (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK)cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TILs) anddendritic cell (DC s).

In some embodiments, the pharmaceutical composition is thepharmaceutical composition wherein the additional therapeutic agentcomprises one or more chimeric antigen receptors (CARs).

In some embodiments, the pharmaceutical composition is thepharmaceutical composition wherein the additional therapeutic agentcomprises an immunotherapy, an immunostimulatory therapy, a cytokinetherapy, a chemokine therapy, a cellular therapy, a gene therapy, orcombinations thereof. In some embodiments, the immunotherapy includesco-administering one or more antibodies or antigen-binding antibodyfragments thereof, or antibody-drug conjugates thereof, CD3-targetingmulti-specific molecules, CD16-targeting multi-specific molecules, ornon-immunoglobulin antigen-binding domains or antibody mimetic proteinsdirected against one or more targets or tumor associated antigens(TAAs).

In some embodiments, compounds disclosed herein are formulated withconventional carriers and excipients, which can be selected in accordwith ordinary practice. Tablets can contain excipients, glidants,fillers, binders and the like. Aqueous formulations can be prepared insterile form, and can be isotonic, for instance when intended fordelivery by other than oral administration. In some embodiments,formulations can optionally contain excipients such as those set forthin the “Handbook of Pharmaceutical Excipients” (1986). Excipients caninclude, for example, ascorbic acid and other antioxidants, chelatingagents such as EDTA, carbohydrates such as dextran,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, forexample from about 7 to about 10.

In some embodiments, the compounds disclosed herein are administeredalone. In some embodiments, compounds disclosed herein are administeredin pharmaceutical formulations. In some embodiments a formulation, forveterinary and/or for human use, comprises at least one compound ofFormula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g),(II-h), (III-a), (III-b), (III-c), or (III-d), or a pharmaceuticallyacceptable salt thereof, together with one or more acceptable carriersand optionally other therapeutic ingredients, such as those additionaltherapeutic ingredients discussed herein. In some embodiments,carrier(s) are “acceptable” in the sense of being compatible with theother ingredients of the formulation and physiologically innocuous tothe recipient thereof.

In some embodiments, formulations of the disclosure include thosesuitable for the foregoing administration routes. In some embodiments,formulations are presented in unit dosage form. Formulations may beprepared by methods known in the art of pharmacy. Techniques andformulations can be found, for example, in Remington's PharmaceuticalSciences (Mack Publishing Co., Easton, PA). Such methods include, forinstance, a step of bringing into association the active ingredient witha carrier comprising one or more accessory ingredients. In someembodiments, formulations are prepared by bringing into association theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, in some embodiments, shaping the product.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets each containing apredetermined amount of active ingredient, such as a compound of Formula(I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h),(III-a), (III-b), (III-c), or (III-d), or a pharmaceutically acceptablesalt thereof; as a powder or granules; as a solution or a suspension inan aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsionor a water-in-oil liquid emulsion. In some embodiments, an activeingredient is administered as a bolus, electuary or paste.

A tablet can be made, for example, by compression or molding, optionallywith one or more accessory ingredients. Compressed tablets may beprepared, for example, by compressing in a suitable machine the activeingredient in a free-flowing form such as a powder or granules,optionally mixed with a binder, lubricant, inert diluent, preservative,surface active or dispersing agent. Molded tablets may be made, forinstance, by molding in a suitable machine a mixture of the powderedactive ingredient moistened with an inert liquid diluent. The tabletsmay optionally be coated or scored. In some embodiments, tablets areformulated so as to provide slow or controlled release of the activeingredient therefrom.

For infections of the eye or other external tissues e.g. mouth and skin,the formulations can be applied as a topical ointment or creamcontaining a compound of Formula (I), (II-a), (II-b), (II-c), (II-d),(II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or (III-d),in an amount of, for example, about 0.075 to about 20% w/w (includingactive ingredient(s) in a range between about and about 20% inincrements of about 0.1% w/w such as about 0.6% w/w, about 0.7% w/w,etc.), such as about 0.2 to about 15% w/w and such as about 0.5 to about10% w/w. When formulated in an ointment, a compound of Formula (I),(II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a),(III-b), (III-c), or (III-d), or a pharmaceutically acceptable saltthereof, may be employed with either a paraffinic or a water-miscibleointment base. Alternatively, a compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d), or a pharmaceutically acceptable salt thereof, maybe formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, forexample, at least about 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations mayin some embodiments include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.

The oily phase of the emulsions may be constituted from knowningredients in a known manner. While the phase may comprise merely anemulsifier (otherwise known as an emulgent), it can comprise, forexample, a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. In some embodiments, a hydrophilicemulsifier is included together with a lipophilic emulsifier which actsas a stabilizer. In some embodiments, an emulsion includes both an oiland a fat. Together, the emulsifier(s) with or without stabilizer(s)make up the so-called emulsifying wax, and the wax together with the oiland fat make up the so-called emulsifying ointment base which forms theoily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationinclude, for instance, Tween® 60, Span® 80, cetostearyl alcohol, benzylalcohol, myristyl alcohol, glyceryl mono-stearate and sodium laurylsulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired properties. The cream can be a non-greasy,non-staining and washable product with suitable consistency to avoidleakage from tubes or other containers. Straight or branched chain,mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate,propylene glycol diester of coconut fatty acids, isopropyl myristate,decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexylpalmitate or a blend of branched chain esters known as Crodamol CAP maybe used. These may be used alone or in combination depending on theproperties required. Alternatively, high melting point lipids such aswhite soft paraffin and/or liquid paraffin or other mineral oils can beused.

In some embodiments, pharmaceutical formulations herein comprise acombination together with one or more pharmaceutically acceptablecarriers or excipients and optionally other therapeutic agents.Pharmaceutical formulations containing the active ingredient may be inany form suitable for the intended method of administration. When usedfor oral use for example, tablets, troches, lozenges, aqueous or oilsuspensions, dispersible powders or granules, emulsions, hard or softcapsules, solutions, syrups or elixirs may be prepared. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents including sweetening agents,flavoring agents, coloring agents and preserving agents, in order toprovide a palatable preparation. Tablets containing the activeingredient in admixture with non-toxic pharmaceutically acceptableexcipient which are suitable for manufacture of tablets are acceptable.These excipients may be, for example, inert diluents, such as calcium orsodium carbonate, lactose, calcium or sodium phosphate; granulating anddisintegrating agents, such as maize starch, or alginic acid; bindingagents, such as starch, gelatin or acacia; and lubricating agents, suchas magnesium stearate, stearic acid or talc. Tablets may be uncoated ormay be coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally-occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, a suspending agent, andone or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those disclosed above. Additionalexcipients, for example sweetening, flavoring and coloring agents, mayalso be present.

The pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, such as olive oil orarachis oil, a mineral oil, such as liquid paraffin, or a mixture ofthese. Suitable emulsifying agents include naturally-occurring gums,such as gum acacia and gum tragacanth, naturally-occurring phosphatides,such as soybean lecithin, esters or partial esters derived from fattyacids and hexitol anhydrides, such as sorbitan monooleate, andcondensation products of these partial esters with ethylene oxide, suchas polyoxyethylene sorbitan monooleate. The emulsion may also containsweetening and flavoring agents. Syrups and elixirs may be formulatedwith sweetening agents, such as glycerol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, a flavoringor a coloring agent.

The pharmaceutical compositions may be in the form of a sterileinjectable or intravenous preparation, such as a sterile injectableaqueous or oleaginous suspension. Such suspensions may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Sterileinjectable or intravenous preparations may also include a sterileinjectable solution or suspension in a non-toxic parenterally acceptablediluent or solvent, such as a solution in 1,3-butane-diol or prepared asa lyophilized powder. Among the acceptable vehicles and solvents thatmay be employed are water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile fixed oils may conventionally beemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed, including synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid may likewise be used in thepreparation of injectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form can vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain about 1 to about 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to about 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient can be present in such formulations ina concentration of about 0.5 to about 20%, such as about 0.5 to about10%, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include,for example, lozenges comprising the active ingredient in a flavoredbasis, such as sucrose and acacia or tragacanth; pastilles comprisingthe active ingredient in an inert basis, such as gelatin and glycerin,or sucrose and acacia; and mouthwashes comprising the active ingredientin a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising, for example, cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size, for example, in the range of about 0.1 to about 500microns, such as about 0.5, about 1, about or about 35, etc., which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of cancer as described below.

Another embodiment provides an inhalable composition comprising acompound of Formula (I), (II-a), (II-b), (II-c), (IIIa), or (IIIb), or apharmaceutically acceptable salt thereof. In some embodiments, theinhalable composition is suitable for treating cancer. In someembodiments, pharmaceutically acceptable salts are inorganic acid saltsincluding hydrochloride, hydrobromide, sulfate or phosphate salts. Forexample, such salts may cause less pulmonary irritation relative toother salts. In some embodiments, an inhalable composition is deliveredto the endobronchial space in an aerosol comprising particles with amass median aerodynamic diameter (MMAD) between about 1 and about 5 μm.In some embodiments, the compound of Formula (I), (II-a), (II-b),(II-c), (IIIa), or (IIIb), or a pharmaceutically acceptable saltthereof, is formulated for aerosol delivery using a nebulizer,pressurized metered dose inhaler (pMDI), or dry powder inhaler (DPI).

Non-limiting examples of nebulizers include atomizing, jet, ultrasonic,pressurized, vibrating porous plate, or equivalent nebulizers includingthose nebulizers utilizing adaptive aerosol delivery technology (Denyer,J. Aerosol medicine Pulmonary Drug Delivery 2010, 23 Supp 1, S1-S10). Ajet nebulizer utilizes air pressure to break a liquid solution intoaerosol droplets. An ultrasonic nebulizer works by a piezoelectriccrystal that shears a liquid into small aerosol droplets. A pressurizednebulization system forces solution under pressure through small poresto generate aerosol droplets. A vibrating porous plate device utilizesrapid vibration to shear a stream of liquid into appropriate dropletsizes.

In another embodiment, a formulation for nebulization is delivered tothe endobronchial space in an aerosol comprising particles with a MMADpredominantly between about 1 μm and about 5 μm using a nebulizer ableto aerosolize the formulation of the compound of Formula (I), (II-a),(II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a),(III-b), (III-c), or (III-d), or a pharmaceutically acceptable saltthereof, into particles of the required MMAD. To be optimallytherapeutically effective and to avoid upper respiratory and systemicside effects, the majority of aerosolized particles should not have aMMAD greater than about 5 μm. If an aerosol contains a large number ofparticles with a MMAD larger than about 5 μm, the particles aredeposited in the upper airways decreasing the amount of drug deliveredto the site of inflammation and bronchoconstriction in the lowerrespiratory tract. If the MMAD of the aerosol is smaller than about 1μm, then the particles can in some cases remain suspended in the inhaledair and may be subsequently exhaled during expiration.

When formulated and delivered according to methods herein, the aerosolformulation for nebulization delivers a therapeutically efficacious doseof the compound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e),(II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or (III-d), or apharmaceutically acceptable salt thereof, to a therapeutic target, suchas the site of a cancer. The amount of drug administered can be adjustedto reflect the efficiency of the delivery of a therapeuticallyefficacious dose of the compound of Formula (I), (II-a), (II-b), (II-c),(II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or(III-d), or a pharmaceutically acceptable salt thereof. In anembodiment, a combination of the aqueous aerosol formulation with theatomizing, jet, pressurized, vibrating porous plate, or ultrasonicnebulizer permits, depending on the nebulizer, from about 20 to about90%, such as about 70% delivery of the administered dose of the compoundof Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g),(II-h), (III-a), (III-b), (III-c), or (III-d), or a pharmaceuticallyacceptable salt thereof, into the airways. In an embodiment, from about30 to about 50% of the active compound is delivered. For example, fromabout 70 to about 90% of the active compound can be delivered.

In another embodiment, a compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d), or a pharmaceutically acceptable salt thereof, isdelivered as a dry inhalable powder. The compounds are administeredendobronchially as a dry powder formulation to efficacious deliver fineparticles of compound into the endobronchial space using dry powder ormetered dose inhalers. For delivery by DPI, the compound of Formula (I),(II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a),(III-b), (III-c), or (III-d), or a pharmaceutically acceptable saltthereof, is processed into particles with, predominantly, MMAD betweenabout 1 μm and about 5 μm by milling spray drying, critical fluidprocessing, or precipitation from solution. Media milling, jet millingand spray-drying devices and procedures capable of producing theparticle sizes with a MMAD between about 1 μm and about 5 μm are wellknown in the art. In one embodiment, excipients are added to thecompound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f),(II-g), (II-h), (III-a), (III-b), (III-c), or (III-d), or apharmaceutically acceptable salt thereof, before processing intoparticles of the required sizes. In another embodiment, excipients areblended with the particles of the required size to aid in dispersion ofthe drug particles, for example by using lactose as an excipient.

Particle size determinations are made using devices well known in theart. For example, a multi-stage Anderson cascade impactor or othersuitable method such as those specifically cited within the USPharmacopoeia Chapter 601 as characterizing devices for aerosols withinmetered-dose and dry powder inhalers.

In another embodiment, a compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d), or a pharmaceutically acceptable salt thereof, canbe delivered as a dry powder using a device such as a dry powder inhaleror other dry powder dispersion devices. Non-limiting examples of drypowder inhalers and devices include those disclosed in U.S. Pat. Nos.5,458,135; 5,740,794; 5,775,320; 5,785,049; 3,906,950; 4,013,075;4,069,819; 4,995,385; 5,522,385; 4,668,218; 4,667,668; 4,805,811 and5,388,572. There are two major designs of dry powder inhalers. Onedesign is a metering device in which a reservoir for the drug is placewithin the device and the patient adds a dose of the drug into theinhalation chamber. The second design is a factory-metered device inwhich each individual dose has been manufactured in a separatecontainer. Both systems depend on the formulation of the drug into smallparticles of MMAD from about 1 μm to about 5 μm and often involveco-formulation with larger excipient particles such as, but not limitedto, lactose. Drug powder is placed in the inhalation chamber (either bydevice metering or by breakage of a factory-metered dosage) and theinspiratory flow of the patient accelerates the powder out of the deviceand into the oral cavity. Non-laminar flow characteristics of the powderpath cause the excipient-drug aggregates to decompose, and the mass ofthe large excipient particles causes their impaction at the back of thethroat, while the smaller drug particles are deposited deep in thelungs. In some embodiments, a compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d), or a pharmaceutically acceptable salt thereof, isdelivered as a dry powder using either type of dry powder inhaler asdescribed herein, wherein the MMAD of the dry powder, exclusive of anyexcipients, is predominantly in the range of about 1 μm to about 5 μm.

In another embodiment, a compound of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d), or a pharmaceutically acceptable salt thereof, isdelivered as a dry powder using a metered dose inhaler. Non-limitingexamples of metered dose inhalers and devices include those disclosed inU.S. Pat. Nos. 5,261,538; 5,544,647; 5,622,163; 4,955,371; 3,565,070;3,361,306 and 6,116,234. In some embodiments, a compound of Formula (I),(II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a),(III-b), (III-c), or (III-d), or a pharmaceutically acceptable saltthereof, is delivered as a dry powder using a metered dose inhalerwherein the MMAD of the dry powder, exclusive of any excipients, ispredominantly in the range of about 1 to about 5 μm.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Unit dosage formulations include those containinga daily dose or unit daily sub-dose, as herein above recited, or anappropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

Further provided are veterinary compositions comprising at least oneactive ingredient as above defined together with a veterinary carriertherefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds herein are used to provide controlled release pharmaceuticalformulations containing as active ingredient one or more of thecompounds (“controlled release formulations”) in which the release ofthe active ingredient is controlled and regulated to allow lessfrequency dosing or to improve the pharmacokinetic or toxicity profileof a given active ingredient.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, the method of delivery, and thepharmaceutical formulation, and can be determined by the clinician usingconventional dose escalation studies. It can be expected to be fromabout 0.0001 to about 100 mg/kg body weight per day; typically, fromabout 0.01 to about mg/kg body weight per day; more typically, fromabout 0.01 to about 5 mg/kg body weight per day; most typically, fromabout 0.05 to about 0.5 mg/kg body weight per day. For example, thedaily candidate dose for an adult human of about 70 kg body weight canrange from about 1 mg to about 1000 mg, such as between about 5 mg andabout 500 mg, and may take the form of single or multiple doses.

Some embodiments provide a method for manufacturing a medicament fortreating cancer in a subject in need thereof. In some embodiments, themethod for manufacturing a medicament for treating cancer includes usinga compound having the structure of Formula (I), (II-a), (II-b), (II-c),(II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or(III-d), or a pharmaceutically acceptable salt thereof. Some embodimentsprovide a method for manufacturing a medicament for inhibiting cancermetastasis in a subject in need thereof. In some embodiments, the methodfor manufacturing a medicament for inhibiting cancer metastasis includesusing a compound having the structure of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disclosure provides a use of compound havingthe structure of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e),(II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or (III-d), or apharmaceutically acceptable salt thereof, in the treatment of cancer ina subject in need thereof. In some embodiments, the disclosure providesa use of compound having the structure of Formula (I), (II-a), (II-b),(II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b),(III-c), or (III-d), or a pharmaceutically acceptable salt thereof, ininhibiting cancer metastasis in a subject in need thereof. In someembodiments, the disclosure provides a compound having the structure ofFormula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g),(II-h), (III-a), (III-b), (III-c), or (III-d), or a pharmaceuticallyacceptable salt thereof, for use in therapy.

IV. Routes of Administration

One or more of the compounds of Formula (I), (II-a), (II-b), (II-c),(II-d), (II-e), (II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or(III-d), or a pharmaceutically acceptable salt thereof, (herein referredto as the active ingredients) are administered by any route appropriateto the condition to be treated. Suitable routes include oral, rectal,nasal, pulmonary, topical (including buccal and sublingual), vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the route may vary with for example the condition ofthe recipient. In some embodiments, compounds disclosed herein areorally bioavailable and can be dosed orally.

The compounds of the present disclosure (also referred to herein as theactive ingredients), can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the route may vary with for example the condition ofthe recipient. An advantage of certain compounds disclosed herein isthat they are orally bioavailable and can be dosed orally.

A compound of the present disclosure, may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer. In some embodiments, the compound isadministered on a daily or intermittent schedule for the duration of theindividual's life.

The dosage or dosing frequency of a compound of the present disclosuremay be adjusted over the course of the treatment, based on the judgmentof the administering physician.

The compound may be administered to an individual (e.g., a human) in aneffective amount. In some embodiments, the compound is administered oncedaily.

The compound can be administered by any useful route and means, such asby oral or parenteral (e.g., intravenous) administration.Therapeutically effective amounts of the compound may include from about0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day,such as from about 0.0001 mg/kg body weight per day to about 10 mg/kgbody weight per day, or such as from about 0.001 mg/kg body weight perday to about 1 mg/kg body weight per day, or such as from about 0.01mg/kg body weight per day to about 1 mg/kg body weight per day, or suchas from about 0.05 mg/kg body weight per day to about 0.5 mg/kg bodyweight per day, or such as from about 0.3 mg to about 30 mg per day, orsuch as from about 30 mg to about 300 mg per day.

A compound of the present disclosure may be combined with one or moreadditional therapeutic agents in any dosage amount of the compound ofthe present disclosure (e.g., from about 1 mg to about 1000 mg ofcompound). Therapeutically effective amounts may include from about 1 mgper dose to about 1000 mg per dose, such as from about 50 mg per dose toabout 500 mg per dose, or such as from about 100 mg per dose to about400 mg per dose, or such as from about 150 mg per dose to about 350 mgper dose, or such as from about 200 mg per dose to about 300 mg perdose. Other therapeutically effective amounts of the compound of thepresent disclosure are about 100, about 125, about 150, about 175, about200, about 225, about 250, about 275, about 300, about 325, about 350,about 375, about 400, about 425, about 450, about 475, or about 500 mgper dose. Other therapeutically effective amounts of the compound of thepresent disclosure are about 100 mg per dose, or about 125, about 150,about 175, about 200, about 225, about 250, about 275, about 300, about325, about 350, about 375, about 400, about 425, about 450, or about 500mg per dose. A single dose can be administered hourly, daily, or weekly.For example, a single dose can be administered once about every 1 hour,about 2, about 3, about 4, about 6, about 8, about 12, about 16 or onceabout every 24 hours. A single dose can also be administered once aboutevery 1 day, about 2, about 3, about 4, about 5, about 6, or once aboutevery 7 days. A single dose can also be administered once about every 1week, about 2, about 3, or once about every 4 weeks. In someembodiments, a single dose can be administered once about every week. Asingle dose can also be administered once about every month.

Other therapeutically effective amounts of the compound of the presentdisclosure are about 20, about 25, about 30, about 35, about 40, about45, about 50, about 55, about 60, about about 70, about 75, about 80,about 85, about 90, about 95, or about 100 mg per dose.

The frequency of dosage of the compound of the present disclosure can bedetermined by the needs of the individual patient and can be, forexample, once per day or twice, or more times, per day. Administrationof the compound continues for as long as necessary to treat the diseaseor condition. For example, a compound can be administered to a humanhaving cancer for a period of from about 20 days to about 180 days or,for example, for a period of from about days to about 90 days or, forexample, for a period of from about 30 days to about 60 days.

Administration can be intermittent, with a period of several or moredays during which a patient receives a daily dose of the compound of thepresent disclosure followed by a period of several or more days duringwhich a patient does not receive a daily dose of the compound. Forexample, a patient can receive a dose of the compound every other day,or three times per week. Again by way of example, a patient can receivea dose of the compound each day for a period of from about 1 to about 14days, followed by a period of about 7 to about 21 days during which thepatient does not receive a dose of the compound, followed by asubsequent period (e.g., from about 1 to about 14 days) during which thepatient again receives a daily dose of the compound. Alternating periodsof administration of the compound, followed by non-administration of thecompound, can be repeated as clinically required to treat the patient.

In one embodiment, pharmaceutical compositions comprising a compound ofthe present disclosure, or a pharmaceutically acceptable salt thereof,in combination with one or more (e.g., one, two, three, four, one ortwo, one to three, or one to four) additional therapeutic agents, and apharmaceutically acceptable excipient are provided.

In one embodiment, kits comprising a compound of the present disclosure,or a pharmaceutically acceptable salt thereof, in combination with oneor more (e.g., one, two, three, four, one or two, one to three, or oneto four) additional therapeutic agents are provided.

In some embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with one, two,three, four or more additional therapeutic agents. In some embodiments,a compound of the present disclosure, or a pharmaceutically acceptablesalt thereof, is combined with two additional therapeutic agents. Inother embodiments, a compound of the present disclosure, or apharmaceutically acceptable salt thereof, is combined with threeadditional therapeutic agents. In further embodiments, a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, iscombined with four additional therapeutic agents. The one, two, three,four or more additional therapeutic agents can be different therapeuticagents selected from the same class of therapeutic agents, and/or theycan be selected from different classes of therapeutic agents.

In some embodiments, when a compound of the present disclosure iscombined with one or more additional therapeutic agents as describedherein, the components of the composition are administered as asimultaneous or sequential regimen. When administered sequentially, thecombination may be administered in two or more administrations.

In some embodiments, a compound of the present disclosure is combinedwith one or more additional therapeutic agents in a unitary dosage formfor simultaneous administration to a patient, for example as a soliddosage form for oral administration.

In some embodiments, a compound of the present disclosure isco-administered with one or more additional therapeutic agents.

In order to prolong the effect of a compound of the present disclosure,it is often desirable to slow the absorption of a compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending a compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of a compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping a compoundin liposomes or microemulsions that are compatible with body tissues.

V. Combination Therapy

The compounds of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e),(II-f), (II-g), (II-h), (III-a), (III-b), (III-c), or (III-d),pharmaceutically acceptable salts thereof, and/or compositions providedherein can also used in combination with other active therapeutic agentsfor the treatment of cancer.

A. COMBINATION THERAPIES

In various embodiments, a compound as described herein, is combined withone or more additional therapeutic agents, e.g., an inhibitory immunecheckpoint blocker or inhibitor, a stimulatory immune checkpointstimulator, agonist or activator, a chemotherapeutic agent, ananti-cancer agent, a radiotherapeutic agent, an anti-neoplastic agent,an anti-proliferation agent, an anti-angiogenic agent, ananti-inflammatory agent, an immunotherapeutic agent, a therapeuticantigen-binding molecule (mono- and multi-specific antibodies andfragments thereof in any format (e.g., including without limitationDARTs®, Duobodies®, BiTEs®, BiKEs, TriKEs, XmAbs®, TandAbs®, scFvs,Fabs, Fab derivatives), bi-specific antibodies, non-immunoglobulinantibody mimetics (e.g., including without limitation adnectins,affibody molecules, affilins, affimers, affitins, alphabodies,anticalins, peptide aptamers, armadillo repeat proteins (ARMs),atrimers, avimers, designed ankyrin repeat proteins (DARPins®),fynomers, knottins, Kunitz domain peptides, monobodies, and nanoCLAMPs),antibody-drug conjugates (ADC), antibody-peptide conjugate), anoncolytic virus, a gene modifier or editor, a cell comprising a chimericantigen receptor (CAR), e.g., including a T-cell immunotherapeuticagent, an NK-cell immunotherapeutic agent, or a macrophageimmunotherapeutic agent, a cell comprising an engineered T-cell receptor(TCR-T), or any combination thereof.

Illustrative Targets

In some embodiments, the one or more additional therapeutic agentsinclude, without limitation, an inhibitor, agonist, antagonist, ligand,modulator, stimulator, blocker, activator or suppressor of a target(e.g., polypeptide or polynucleotide) including without limitation:Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such asABL1), Acetyl-CoA carboxylase (such as ACC1/2), activated CDC kinase(ACK, such as ACK1), Adenosine deaminase, adenosine receptor (such asA2BR, A2aR, A3aR), Adenylate cyclase, ADP ribosyl cyclase-1,adrenocorticotropic hormone receptor (ACTH), Aerolysin, AKT1 gene, Alk-5protein kinase, Alkaline phosphatase, Alpha 1 adrenoceptor, Alpha 2adrenoceptor, Alpha-ketoglutarate dehydrogenase (KGDH), AminopeptidaseN, AMP activated protein kinase, anaplastic lymphoma kinase (ALK, suchas ALK1), Androgen receptor, Angiopoietin (such as ligand-1, ligand-2),Angiotensinogen (AGT) gene, murine thymoma viral oncogene homolog 1(AKT) protein kinase (such as AKT1, AKT2, AKT3), apolipoprotein A-I(APOA1) gene, Apoptosis inducing factor, apoptosis protein (such as 1,2), apoptosis signal-regulating kinase (ASK, such as ASK1), Arginase(I), Arginine deiminase, Aromatase, Asteroid homolog 1 (ASTE1) gene,ataxia telangiectasia and Rad 3 related (ATR) serine/threonine proteinkinase, Aurora protein kinase (such as 1, 2), Ax1 tyrosine kinasereceptor, 4-1BB ligand (CD137L), Baculoviral IAP repeat containing 5(BIRC5) gene, Basigin, B-cell lymphoma 2 (BCL2) gene, Bcl2 bindingcomponent 3, Bcl2 protein, BCL2L11 gene, BCR (breakpoint cluster region)protein and gene, Beta adrenoceptor, Beta-catenin, B-lymphocyte antigenCD19, B-lymphocyte antigen CD20, B-lymphocyte cell adhesion molecule,B-lymphocyte stimulator ligand, Bone morphogenetic protein-10 ligand,Bone morphogenetic protein-9 ligand modulator, Brachyury protein,Bradykinin receptor, B-Raf proto-oncogene (BRAF), Brc-Abl tyrosinekinase, Bromodomain and external domain (BET) bromodomain containingprotein (such as BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK),Calmodulin, calmodulin-dependent protein kinase (CaMK, such as CAMKII),Cancer testis antigen 2, Cancer testis antigen NY-ESO-1, cancer/testisantigen 1B (CTAG1) gene, Cannabinoid receptor (such as CB1, CB2),Carbonic anhydrase, casein kinase (CK, such as CKI, CKII), Caspase (suchas caspase-3, caspase-7, Caspase-9), caspase 8 apoptosis-relatedcysteine peptidase CASP8-FADD-like regulator, Caspase recruitment domainprotein-15, Cathepsin G, CCR5 gene, CDK-activating kinase (CAK),Checkpoint kinase (such as CHK1, CHK2), chemokine (C—C motif) receptor(such as CCR², CCR4, CCR5, CCR8), chemokine (C—X—C motif) receptor (suchas CXCR1, CXCR², CXCR3 and CXCR4), Chemokine CC21 ligand,Cholecystokinin CCK2 receptor, Chorionic gonadotropin, c-Kit(tyrosine-protein kinase Kit or CD117), CISH (Cytokine-inducibleSH2-containing protein), Claudin (such as 6, 18), cluster ofdifferentiation (CD) such as CD4, CD27, CD29, CD30, CD33, CD37, CD40,CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b,CD51, CD52, CD55, CD58, CD66e (CEACAM6), CD70 gene, CD74, CD79, CD79b,CD79B gene, CD80, CD95, CD99, CD117, CD122, CDw123, CD134, CDw137,CD158a, CD158b1, CD158b2, CD223, CD276 antigen; clusterin (CLU) gene,Clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), ComplementC3, Connective tissue growth factor, COPS signalosome subunit 5, CSF-1(colony-stimulating factor 1 receptor), CSF2 gene, CTLA-4 (cytotoxicT-lymphocyte protein 4) receptor, C-type lectin domain protein 9A(CLEC9A), Cyclin D1, Cyclin G1, cyclin-dependent kinases (CDK, such asCDK1, CDK12, CDK1B, CDK2-9), cyclooxygenase (such as COX1, COX2), CYP2B1gene, Cysteine palmitoyltransferase porcupine, Cytochrome P450 11B2,Cytochrome P450 17, cytochrome P450 17A1, Cytochrome P450 2D6,cytochrome P450 3A4, Cytochrome P450 reductase, cytokine signalling-1,cytokine signalling-3, Cytoplasmic isocitrate dehydrogenase, Cytosinedeaminase, cytosine DNA methyltransferase, cytotoxic T-lymphocyteprotein-4, DDR2 gene, DEAD-box helicase 6 (DDX6), Death receptor 5 (DR5,TRAILR2), Death receptor 4 (DR4, TRAILR1), Delta-like protein ligand(such as 3, 4), Deoxyribonuclease, Deubiquitinating enzymes (DUB s),Dickkopf-1 ligand, dihydrofolate reductase (DHFR), Dihydropyrimidinedehydrogenase, Dipeptidyl peptidase IV, discoidin domain receptor (DDR,such as DDR1), Diacylglycerol kinase zeta (DGKZ), DNA binding protein(such as HU-beta), DNA dependent protein kinase, DNA gyrase, DNAmethyltransferase, DNA polymerase (such as alpha), DNA primase, dUTPpyrophosphatase, L-dopachrome tautomerase, E3 ubiquitin-protein ligase(such as RNF128, CBL-B), echinoderm microtubule like protein 4, EGFRtyrosine kinase receptor, Elastase, Elongation factor 1 alpha 2,Elongation factor 2, Endoglin, Endonuclease, endoplasmic reticulumaminopeptidase (ERAP, such as ERAP 1, ERAP2), Endoplasmin, Endosialin,Endostatin, endothelin (such as ET-A, ET-B), Enhancer of zeste homolog 2(EZH2), Ephrin (EPH) tyrosine kinase (such as Epha3, Ephb4), Ephrin B2ligand, epidermal growth factor, epidermal growth factor receptors(EGFR), epidermal growth factor receptor (EGFR) gene, Epigen, Epithelialcell adhesion molecule (EpCAM), Erb-b2 (v-erb-b2 avian erythroblasticleukemia viral oncogene homolog 2) tyrosine kinase receptor, Erb-b3tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin,Estradiol 17 beta dehydrogenase, Estrogen receptor (such as alpha,beta), Estrogen related receptor, Eukaryotic translation initiationfactor 5A (EIF5A) gene, Exportin 1, Extracellular signal related kinase(such as 1, 2), Extracellular signal-regulated kinases (ERK),Hypoxia-inducible factor prolyl hydroxylase (HIF-PH or EGLN), Factor(such as Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, Fatty acidsynthase (FASN), Ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growthfactor (FGF, such as FGF1, FGF2, FGF4), Fibronectin, focal adhesionkinase (FAK, such as FAK2), folate hydrolase prostate-specific membraneantigen 1 (FOLH1), Folate receptor (such as alpha), Folate, Folatetransporter 1, FYN tyrosine kinase, paired basic amino acid cleavingenzyme (FURIN), Beta-glucuronidase, Galactosyltransferase, Galectin-3,Ganglioside GD2, Glucocorticoid, glucocorticoid-induced TNFR-relatedprotein GITR receptor, Glutamate carboxypeptidase II, glutaminase,Glutathione S-transferase P, glycogen synthase kinase (GSK, such as3-beta), Glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH),Granulocyte macrophage colony stimulating factor (GM-CSF) receptor,Granulocyte-colony stimulating factor (GCSF) ligand, growth factorreceptor-bound protein 2 (GRB2), Grp78 (78 kDa glucose-regulatedprotein) calcium binding protein, molecular chaperone groEL2 gene, Hemeoxygenase 1 (H01), Heme oxygenase 2 (HO2), Heat shock protein (such as27, 70, 90 alpha, beta), Heat shock protein gene, Heat stableenterotoxin receptor, Hedgehog protein, Heparanase, Hepatocyte growthfactor, HERV-H LTR associating protein 2, Hexose kinase, Histamine H2receptor, Histone methyltransferase (DOT1L), histone deacetylase (HDAC,such as 1, 2, 3, 6, 10, 11), Histone H1, Histone H3, HLA class I antigen(A-2 alpha), HLA class II antigen, HLA class I antigen alpha G (HLA-G),Non-classical HLA, Homeobox protein NANOG, HSPB1 gene, Human leukocyteantigen (HLA), Human papillomavirus (such as E6, E7) protein, Hyaluronicacid, Hyaluronidase, Hypoxia inducible factor-1 alpha (HIF1α), ImprintedMaternally Expressed Transcript (H19) gene, mitogen-activated proteinkinase 1 (MAP4K1), tyrosine-protein kinase HCK, I-Kappa-B kinase (IKK,such as IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15, IL-17,IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6,IL-7, IL-8, immunoglobulin (such as G, G1, G2, K, M), Immunoglobulin Fcreceptor, Immunoglobulin gamma Fc receptor (such as I, III, IIIA),indoleamine 2,3-dioxygenase (IDO, such as IDO1 and IDO2), indoleaminepyrrole 2,3-dioxygenase 1 inhibitor, insulin receptor, Insulin-likegrowth factor (such as 1, 2), Integrin alpha-4/beta-1, integrinalpha-4/beta-7, Integrin alpha-5/beta-1, Integrin alpha-V/beta-3,Integrin alpha-V/beta-5, Integrin alpha-V/beta-6, Intercellular adhesionmolecule 1 (ICAM-1), interferon (such as alpha, alpha 2, beta, gamma),Interferon inducible protein absent in melanoma 2 (AIM2), interferontype I receptor, Interleukin 1 ligand, Interleukin 13 receptor alpha 2,interleukin 2 ligand, interleukin-1 receptor-associated kinase 4(IRAK4), Interleukin-2, Interleukin-29 ligand, Interleukin 35 (IL-35),isocitrate dehydrogenase (such as IDH1, IDH2), Janus kinase (JAK, suchas JAK1, JAK2), Jun N terminal kinase, kallikrein-related peptidase 3(KLK3) gene, Killer cell Ig like receptor, Kinase insert domain receptor(KDR), Kinesin-like protein KIF11, Kirsten rat sarcoma viral oncogenehomolog (KRAS) gene, Kisspeptin (KiSS-1) receptor, KIT gene, v-kitHardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) tyrosinekinase, lactoferrin, Lanosterol-14 demethylase, LDL receptor relatedprotein-1, Leukocyte immunoglobulin-like receptor subfamily B member 1(ILT2), Leukocyte immunoglobulin-like receptor subfamily B member 2(ILT4), Leukotriene A4 hydrolase, Listeriolysin, L-Selectin, Luteinizinghormone receptor, Lyase, lymphocyte activation gene 3 protein (LAG-3),Lymphocyte antigen 75, Lymphocyte function antigen-3 receptor,lymphocyte-specific protein tyrosine kinase (LCK), Lymphotactin, Lyn(Lck/Yes novel) tyrosine kinase, lysine demethylases (such as KDM1,KDM2, KDM4, KDM5, KDM6, A/B/C/D), Lysophosphatidate-1 receptor,lysosomal-associated membrane protein family (LAMP) gene, Lysyl oxidasehomolog 2, lysyl oxidase protein (LOX), 5-Lipoxygenase (5-LOX),Hematopoietic Progenitor Kinase 1 (HPK1), Hepatocyte growth factorreceptor (MET) gene, macrophage colony-stimulating factor (MCSF) ligand,Macrophage migration inhibitory fact, MAGEC1 gene, MAGEC2 gene, Majorvault protein, MAPK-activated protein kinase (such as MK2), Mas-relatedG-protein coupled receptor, matrix metalloprotease (MMP, such as MMP2,MMP9), Mc1-1 differentiation protein, Mdm2 p53-binding protein, Mdm4protein, Melan-A (MART-1) melanoma antigen, Melanocyte protein Pmel 17,melanocyte stimulating hormone ligand, melanoma antigen family A3(MAGEA3) gene, Melanoma associated antigen (such as 1, 2, 3, 6),Membrane copper amine oxidase, Mesothelin, MET tyrosine kinase,Metabotropic glutamate receptor 1, Metalloreductase STEAP1 (sixtransmembrane epithelial antigen of the prostate 1), Metastin,methionine aminopeptidase-2, Methyltransferase, Mitochondrial 3 ketoacylCoA thiolase, mitogen-activate protein kinase (MAPK), mitogen-activatedprotein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target ofrapamycin (serine/threonine kinase), mTOR complex (such as 1,2), mucin(such as 1, 5A, 16), mut T homolog (MTH, such as MTH1), Mycproto-oncogene protein, myeloid cell leukemia 1 (MCL1) gene,myristoylated alanine-rich protein kinase C substrate (MARCKS) protein,NAD ADP ribosyltransferase, natriuretic peptide receptor C, Neural celladhesion molecule 1, Neurokinin 1 (NK1) receptor, Neurokinin receptor,Neuropilin 2, NF kappa B activating protein, NIMA-related kinase 9(NEK9), Nitric oxide synthase, NK cell receptor, NK3 receptor, NKG2 A Bactivating NK receptor, NLRP3 (NACHT LRR PYD domain protein 3)modulators, Noradrenaline transporter, Notch (such as Notch-2 receptor,Notch-3 receptor, Notch-4 receptor), Nuclear erythroid 2-related factor2, Nuclear Factor (NF) kappa B, Nucleolin, Nucleophosmin,nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), 2 oxoglutaratedehydrogenase, 2,5-oligoadenylate synthetase, O-methylguanine DNAmethyltransferase, Opioid receptor (such as delta), Ornithinedecarboxylase, Orotate phosphoribosyltransferase, orphan nuclear hormonereceptor NR4A1, Osteocalcin, Osteoclast differentiation factor,Osteopontin, OX-40 (tumor necrosis factor receptor superfamily member 4TNFRSF4, or CD134) receptor, P3 protein, p38 kinase, p38 MAP kinase, p53tumor suppressor protein, Parathyroid hormone ligand, peroxisomeproliferator-activated receptors (PPAR, such as alpha, delta, gamma),P-Glycoprotein (such as 1), phosphatase and tensin homolog (PTEN),phosphatidylinositol 3-kinase (PI3K), phosphoinositide-3 kinase (PI3Ksuch as alpha, delta, gamma), phosphorylase kinase (PK), PKN3 gene,placenta growth factor, platelet-derived growth factor (PDGF, such asalpha, beta), Platelet-derived growth factor (PDGF, such as alpha,beta), Pleiotropic drug resistance transporter, Plexin B1, PLK1 gene,polo-like kinase (PLK), Polo-like kinase 1, Poly (ADP-ribose) polymerase(PARP, such as PARP1, PARP2 and PARP3, PARP7, and mono-PARPs),Preferentially expressed antigen in melanoma (PRAME) gene,Prenyl-binding protein (PrPB), Probable transcription factor PML,Progesterone receptor, Programmed cell death 1 (PD-1), Programmed celldeath ligand 1 inhibitor (PD-L1), Prosaposin (PSAP) gene, Prostanoidreceptor (EP4), Prostaglandin E2 synthase, prostate specific antigen,Prostatic acid phosphatase, proteasome, Protein E7, Proteinfarnesyltransferase, protein kinase (PK, such as A, B, C), proteintyrosine kinase, Protein tyrosine phosphatase beta, Proto-oncogeneserine/threonine-protein kinase (PIM, such as PIM-1, PIM-2, PIM-3),P-Selectin, Purine nucleoside phosphorylase, purinergic receptor P2Xligand gated ion channel 7 (P2X7), Pyruvate dehydrogenase (PDH),Pyruvate dehydrogenase kinase, Pyruvate kinase (PYK), 5-Alpha-reductase,Raf protein kinase (such as 1, B), RAF1 gene, Ras gene, Ras GTPase, RETgene, Ret tyrosine kinase receptor, retinoblastoma associated protein,retinoic acid receptor (such as gamma), Retinoid X receptor, Rheb (Rashomolog enriched in brain) GTPase, Rho (Ras homolog) associated proteinkinase 2, ribonuclease, Ribonucleotide reductase (such as M2 subunit),Ribosomal protein S6 kinase, RNA polymerase (such as I, II), Ron(Recepteur d'Origine Nantais) tyrosine kinase, ROS1 (ROS proto-oncogene1, receptor tyrosine kinase) gene, Rosl tyrosine kinase, Runt-relatedtranscription factor 3, Gamma-secretase, S100 calcium binding proteinA9, Sarco endoplasmic calcium ATPase, Second mitochondria-derivedactivator of caspases (SMAC) protein, Secreted frizzled relatedprotein-2, Secreted phospholipase A2, Semaphorin-4D, Serine protease,serine/threonine kinase (STK), serine/threonine-protein kinase (TBK,such as TBK1), signal transduction and transcription (STAT, such asSTAT-1, STAT-3, STAT-5), Signaling lymphocytic activation molecule(SLAM) family member 7, six-transmembrane epithelial antigen of theprostate (STEAP) gene, SL cytokine ligand, smoothened (SMO) receptor,Sodium iodide cotransporter, Sodium phosphate cotransporter 2B,Somatostatin receptor (such as 1, 2, 3, 4, 5), Sonic hedgehog protein,Son of sevenless (SOS), Specific protein 1 (Spl) transcription factor,Sphingomyelin synthase, Sphingosine kinase (such as 1, 2),Sphingosine-1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRCgene, Src tyrosine kinase, Stabilin-1 (STAB1), STAT3 gene, Steroidsulfatase, Stimulator of interferon genes (STING) receptor, stimulatorof interferon genes protein, Stromal cell-derived factor 1 ligand, SUMO(small ubiquitin-like modifier), Superoxide dismutase, Suppressor ofcytokine signaling modulators (SOCS), Survivin protein, Synapsin 3,Syndecan-1, Synuclein alpha, T cell surface glycoprotein CD28,tank-binding kinase (TBK), TATA box-binding protein-associated factorRNA polymerase I subunit B (TAF1B) gene, T-cell CD3 glycoprotein zetachain, T-cell differentiation antigen CD6, T-cell immunoglobulin andmucin-domain containing-3 (TIM-3), T-cell surface glycoprotein CD8, Tecprotein tyrosine kinase, Tek tyrosine kinase receptor, telomerase,Telomerase reverse transcriptase (TERT) gene, Tenascin, Three primerepair exonuclease 1 (TREX1), Three prime repair exonuclease 2 (TREX2),Thrombopoietin receptor, Thymidine kinase, Thymidine phosphorylase,Thymidylate synthase, Thymosin (such as alpha 1), Thyroid hormonereceptor, Thyroid stimulating hormone receptor, Tissue factor, TNFrelated apoptosis inducing ligand, TNFR1 associated death domainprotein, TNF-related apoptosis-inducing ligand (TRAIL) receptor, TNFSF11gene, TNFSF9 gene, Toll-like receptor (TLR such as 1-13), topoisomerase(such as I, II, III), Transcription factor, Transferase, transferrin(TF), transforming growth factor alpha (TGFα), transforming growthfactor beta (TGFB) and isoforms thereof, TGF beta 2 ligand, Transforminggrowth factor TGF-β receptor kinase, Transglutaminase, Translocationassociated protein, Transmembrane glycoprotein NMB, Trop-2 calciumsignal transducer, trophoblast glycoprotein (TPBG) gene, Trophoblastglycoprotein, Tropomyosin receptor kinase (Trk) receptor (such as TrkA,TrkB, TrkC), tryptophan 2,3-dioxygenase (TDO), Tryptophan 5-hydroxylase,Tubulin, Tumor necrosis factor (TNF, such as alpha, beta), Tumornecrosis factor 13C receptor, tumor progression locus 2 (TPL2), Tumorprotein 53 (TP53) gene, Tumor suppressor candidate 2 (TUSC2) gene, Tumorspecific neoantigens, Tyrosinase, Tyrosine hydroxylase, tyrosine kinase(TK), Tyrosine kinase receptor, Tyrosine kinase with immunoglobulin-likeand EGF-like domains (TIE) receptor, Tyrosine protein kinase ABL1inhibitor, Ubiquitin, Ubiquitin carboxyl hydrolase isozyme L5, Ubiquitinthioesterase-14, Ubiquitin-conjugating enzyme E2I (UBE2I, UBC9),Ubiquitin-specific-processing protease 7 (USP7), Urease, Urokinaseplasminogen activator, Uteroglobin, Vanilloid VR1, Vascular celladhesion protein 1, vascular endothelial growth factor receptor (VEGFR),V-domain Ig suppressor of T-cell activation (VISTA), VEGF-1 receptor,VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF-B, Vimentin, Vitamin D3receptor, Proto-oncogene tyrosine-protein kinase, Mer (Mer tyrosinekinase receptor modulators), YAP (Yes-associated protein modulators)es,Wee-1 protein kinase, Werner Syndrome RecQ Like Helicase (WRN), Wilms'tumor antigen 1, Wilms' tumor protein, WW domain containingtranscription regulator protein 1 (TAZ), X-linked inhibitor of apoptosisprotein, Zinc finger protein transcription factor or any combinationthereof.

Illustrative Mechanisms of Action

In various embodiments, the one or more additional therapeutic agentsmay be categorized by their mechanism of action into, for example, thefollowing groups:

-   -   anti-metabolites/anti-cancer agents, such as pyrimidine analogs        floxuridine, capecitabine, cytarabine, CPX-351 (liposomal        cytarabine, daunorubicin), and TAS-118;    -   Alpha 1 adrenoceptor/Alpha 2 adrenoceptor antagonists, such as        phenoxybenzamine hydrochloride (injectable, pheochromocytoma);    -   Androgen receptor antagonists, such as nilutamide;    -   anti-cadherin antibodies, such as HKT-288;    -   anti-leucine-rich repeat containing 15 (LRRC15) antibodies, such        as ABB V-085. ARGX-110;    -   angiotensin receptor blockers, nitric oxide donors;    -   antisense oligonucleotides, such as AEG35156, IONIS-KRAS-2.5Rx,        EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen),        IONIS-STAT3-2.5Rx;    -   anti-angiopoietin (ANG)-2 antibodies, such as MEDI3617, and        LY3127804;    -   anti-ANG-1/ANG-2 antibodies, such as AMG-780;    -   anti-CSF1R antibodies, such as emactuzumab, LY3022855, AMG-820,        FPA-008 (cabiralizumab);    -   anti-endoglin antibodies, such as TRC105 (carotuximab);    -   anti-ERBB antibodies, such as CDX-3379, HLX-02, seribantumab;    -   anti-HER2 antibodies, such as HERCEPTIN® (trastuzumab),        trastuzumab biosimimar, margetuximab, MEDI4276, BAT-8001,        Pertuzumab (Perjeta), RG6264, ZW25 (a bispecific HER2-directed        antibody targeting the extracellular domains 2 and 4; Cancer        Discov. 2019 January; 9(1):8; PMID: 30504239);    -   anti-HLA-DR antibodies, such as IMMU-114;    -   anti-IL-3 antibodies, such as JNJ-56022473;    -   anti-TNF receptor superfamily member 18 (TNFRSF18, GITR; NCBI        Gene ID: 8784) antibodies, such as MK-4166, MEDI1873, FPA-154,        INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323; and those        described, e.g. in Intl. Patent Publ. Nos. WO 2017/096179, WO        2017/096276, WO 2017/096189; and WO 2018/089628;    -   anti-EphA3 antibodies, such as KB-004;    -   anti-CD37 antibodies, such as otlertuzumab (TRU-016);    -   anti-FGFR-3 antibodies, such as LY3076226, B-701;    -   anti-FGFR-2 antibodies, such as GAL-F2;    -   anti-05 antibodies, such as ALXN-1210;    -   anti-EpCAM antibodies, such as VB4-845;    -   anti-CEA antibodies, such as RG-7813;    -   anti-Carcinoembryonic-antigen-related-cell-adhesion-molecule-6        (CEACAM6, CD66C) antibodies, such as BAY-1834942, NEO-201        (CEACAM 5/6);    -   anti-GD2 antibodies, such as APN-301;    -   anti-interleukin-17 (IL-17) antibodies, such as CJM-112;    -   anti-interleukin-1 beta antibodies, such as canakinumab        (ACZ885), VPM087;    -   anti-carbonic anhydrase 9 (CA9, CAIX) antibodies, such as        TX-250;    -   anti-CD38 antibodies, such as isatuximab, MOR-202, TAK-079;    -   anti-CD38-attenukine, such as TAK573;    -   anti-Mucin 1 (MUC1) antibodies, such as gatipotuzumab,        Mab-AR-20.5;    -   anti-CD33 antibodies, such as IMGN-779;    -   anti-KMA antibodies, such as MDX-1097;    -   anti-CD55 antibodies, such as PAT-SC1;    -   anti-c-Met antibodies, such as ABBV-399;    -   anti-PSMA antibodies, such as ATL-101;    -   anti-CD100 antibodies, such as VX-15;    -   anti-EPHA3 antibodies, such as fibatuzumab;    -   anti-APRIL antibodies, such as BION-1301;    -   anti-fibroblast activation protein (FAP)/IL-2R antibodies, such        as RG7461;    -   anti-fibroblast activation protein (FAP)/TRAIL-R2 antibodies,        such as RG7386;    -   anti-fucosyl-GM1 antibodies, such as BMS-986012;    -   anti-IL-8 (Interleukin-8) antibodies, such as HuMax-Inflam;    -   anti-myostatin inhibitors, such as landogrozumab;    -   anti-delta-like protein ligand 3 (DDL3) antibodies, such as        rovalpituzumab tesirine;    -   anti-DLL4 (delta like ligand 4) antibodies, such as demcizumab;    -   anti-clusterin antibodies, such as AB-16B5;    -   anti-Ephrin-A4 (EFNA4) antibodies, such as PF-06647263;    -   anti-RANKL antibodies, such as denosumab;    -   anti-mesothelin antibodies, such as BMS-986148, Anti-MSLN-MMAE;    -   anti-sodium phosphate cotransporter 2B (NaP2B) antibodies, such        as lifastuzumab    -   anti-TGFb antibodies, such as SAR439459;    -   anti-transforming growth factor-beta (TGF-beta) antibodies, such        as ABB V-151, LY3022859, NIS793, XOMA 089;    -   purine analogs, folate antagonists (such as pralatrexate),        cladribine, pentostatin, fludarabine and related inhibitors;    -   antiproliferative/antimitotic agents including natural products,        such as vinca alkaloids (vinblastine, vincristine) and        microtubule disruptors such as taxane (paclitaxel, docetaxel),        vinblastin, nocodazole, epothilones, vinorelbine (NAVELBINE®),        and epipodophyllotoxins (etoposide, teniposide);    -   DNA damaging agents, such as actinomycin, amsacrine, busulfan,        carboplatin, chlorambucil, cisplatin, cyclophosphamide        (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, DEBDOX,        epirubicin, iphosphamide, melphalan, merchlorethamine, mitomycin        C, mitoxantrone, nitrosourea, procarbazine, taxol, Taxotere,        teniposide, etoposide, and triethylenethiophosphoramide;    -   DNA-hypomethylating agents, such as guadecitabine (SGI-110),        ASTX727;    -   antibiotics such as dactinomycin, daunorubicin, doxorubicin,        idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin        (mithramycin);    -   enzymes such as L-asparaginase which systemically metabolizes        L-asparagine and deprives cells which do not have the capacity        to synthesize their own asparagine;    -   DNAi oligonucleotides targeting Bcl-2, such as PNT2258; agents        that activate or reactivate latent human immunodeficiency virus        (HIV), such as panobinostat and romidepsin;    -   asparaginase stimulators, such as crisantaspase (Erwinase®) and        GRASPA (ERY-001, ERY-ASP), calaspargase pegol, pegaspargase;    -   pan-Trk, ROS1 and ALK inhibitors, such as entrectinib, TPX-0005;    -   anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib,        ceritinib, alecensa (RG7853), ALUNBRIG® (brigatinib);    -   antiproliferative/antimitotic alkylating agents, such as        nitrogen mustard cyclophosphamide and analogs (e.g., melphalan,        chlorambucil, hexamethylmelamine, thiotepa), alkyl nitrosoureas        (e.g., carmustine) and analogs, streptozocin, and triazenes        (e.g., dacarbazine);    -   antiproliferative/antimitotic antimetabolites, such as folic        acid analogs (methotrexate);    -   platinum coordination complexes (e.g., cisplatin, oxiloplatinim,        and carboplatin), procarbazine, hydroxyurea, mitotane, and        aminoglutethimide;    -   hormones, hormone analogs (e.g., estrogen, tamoxifen, goserelin,        bicalutamide, and nilutamide), and aromatase inhibitors (e.g.,        letrozole and anastrozole);    -   antiplatelet agents; anticoagulants such as heparin, synthetic        heparin salts, and other inhibitors of thrombin;    -   fibrinolytic agents such as tissue plasminogen activator,        streptokinase, urokinase, aspirin, dipyridamole, ticlopidine,        and clopidogrel;    -   antimigratory agents; antisecretory agents (e.g., breveldin);    -   immunosuppressives, such as tacrolimus, sirolimus, azathioprine,        and mycophenolate;    -   growth factor inhibitors, and vascular endothelial growth factor        inhibitors;    -   fibroblast growth factor inhibitors, such as FPA14;    -   AMP activated protein kinase stimulators, such as metformin        hydrochloride;    -   ADP ribosyl cyclase-1 inhibitors, such as daratumumab        (DARZALEX®);    -   Caspase recruitment domain protein-15 stimulators, such as        mifamurtide (liposomal);    -   CCR5 chemokine antagonists, such as MK-7690 (vicriviroc);    -   CDC7 protein kinase inhibitors, such as TAK-931; Cholesterol        side-chain cleavage enzyme inhibitors, such as ODM-209;    -   Dihydropyrimidine dehydrogenase/Orotate        phosphoribosyltransferase inhibitors, such as Cefesone        (tegafur+gimeracil+oteracil potassium);    -   DNA polymerase/Ribonucleotide reductase inhibitors, such as        clofarabine;    -   DNA interference oligonucleotides, such as PNT2258, AZD-9150;        Estrogen receptor modulators, such as bazedoxifene;    -   Estrogen receptor agonists/Progesterone receptor antagonists,        such as TRI-CYCLEN LO (norethindrone+ethinyl estradiol);    -   HLA class I antigen A-2 alpha modulators, such as FH-MCVA2TCR;    -   HLA class I antigen A-2 alpha/MART-1 melanoma antigen        modulators, such as MART-1 F5 TCR engineered PBMC;    -   Human Granulocyte Colony Stimulating Factors, such as        PF-06881894;    -   GNRH receptor agonists, such as leuprorelin acetate, leuprorelin        acetate sustained release depot (ATRIGEL), triptorelin pamoate,        go serelin acetate;    -   GNRH receptor antagonists, such as elagolix, relugolix,        degarelix;    -   Endoplasmin modulators, such as anlotinib;    -   H+K+ATPase inhibitors, such as omeprazole, esomeprazole;    -   ICAM-1/CD55 modulators, such as cavatak (V-937); IL-15/IL-12        modulators, such as SAR441000;    -   Interleukin 23A inhibitors, such as guselkumab;    -   Lysine specific histone demethylase 1 inhibitors, such as        CC-90011;    -   IL-12 Mrna, such as MEDI1191;    -   RIG-I modulators, such as RGT-100;    -   NOD2 modulators, such as SB-9200, and IR-103.    -   Progesterone receptor agonists, such as levonorgestrel;    -   Protein cereblon modulators, such as CC-92480, CC-90009;    -   Protein cereblon modulators/DNA binding protein Ikaros        inhibitors/Zinc finger binding protein Aiolos inhibitors, such        as iberdomide;    -   Retinoid X receptor modulators, such as alitretinoin, bexarotene        (oral formulation);    -   RIP-1 kinase inhibitors, such as GSK-3145095;    -   selective oestrogen receptor degraders, such as AZD9833;    -   SUMO inhibitors, such as TAK-981;    -   Thrombopoietin receptor agonists, such as eltrombopag;    -   Thyroid hormone receptor agonists, such as levothyroxine sodium;    -   TNF agonists, such as tasonermin;    -   Tyrosine phosphatase substrate 1 inhibitors, such as CC-95251;    -   HER2 inhibitors, such as neratinib, tucatinib (ONT-380);    -   EGFR/ErbB2/Ephb4 inhibitors, such as tesevatinib;    -   EGFR/HER2 inhibitors, such as TAK-788;    -   EGFR family tyrosine kinase receptor inhibitors, such as        DZD-9008; EGFR/ErbB-2 inhibitors, such as varlitinib;    -   Mutant selective EGFR inhibitors, such as PF-06747775, EGF816        (nazartinib), ASP8273, ACEA-0010, BI-1482694;    -   epha2 inhibitors, such as MM-310;    -   polycomb protein (EED) inhibitors, such as MAK683;    -   DHFR inhibitor/Folate transporter 1 modulator/Folate receptor        antagonist, such as pralatrexate;    -   DHFR/GAR transformylase/Thymidylate synthase/Transferase        inhibitors, such as pemetrexed disodium;    -   p38 MAP kinase inhibitors, such as ralimetinib;    -   PRMT inhibitors, such as MS203, PF-06939999, GSK3368715,        GSK3326595;    -   Sphingosine kinase 2 (SK2) inhibitors, such as opaganib;    -   Nuclear erythroid 2-related factor 2 stimulators, such as        omaveloxolone (RTA-408);    -   Tropomyosin receptor kinase (TRK) inhibitors, such as LOXO-195,        ONO-7579;    -   Mucin 1 inhibitors, such as GO-203-2C;    -   MARCKS protein inhibitors, such as BIO-11006;    -   Folate antagonists, such as arfolitixorin;    -   Galectin-3 inhibitors, such as GR-MD-02;    -   Phosphorylated P68 inhibitors, such as RX-5902;    -   CD95/TNF modulators, such as ofranergene obadenovec;    -   pan-PIM kinase inhibitors, such as INCB-053914;    -   IL-12 gene stimulators, such as EGEN-001, tavokinogene        telseplasmid;    -   Heat shock protein HSP90 inhibitors, such as TAS-116, PEN-866;    -   VEGF/HGF antagonists, such as MP-0250;    -   VEGF ligand inhibitors, such as bevacizumab biosimilar;    -   VEGF receptor antagonists/VEGF ligand inhibitors, such as        ramucirumab;    -   VEGF-1/VEGF-2/VEGF-3 receptor antagonists; such as fruquintinib;    -   VEGF-1/VEGF-2 receptor modulators, such as HLA-A2402/HLA-A0201        restricted epitope peptide vaccine;    -   Placenta growth factor ligand inhibitor/VEGF-A ligand inhibitor,        such as aflibercept;    -   SYK tyrosine kinase/JAK tyrosine kinase inhibitors, such as        ASN-002;    -   Trk tyrosine kinase receptor inhibitors, such as larotrectinib        sulfate;    -   JAK3/JAK1/TBK1 kinase inhibitors, such as CS-12912;    -   IL-24 antagonist, such as AD-IL24;    -   NLRP3 (NACHT LRR PYD domain protein 3) modulators, such as        BMS-986299;    -   RIG-I agonists, such as RGT-100;    -   Aerolysin stimulators, such as topsalysin;    -   P-Glycoprotein 1 inhibitors, such as HM-30181A;    -   CSF-1 antagonists, such as ARRY-382, BLZ-945;    -   CCR8 inhibitors, such as 1-309, SB-649701, HG-1013, RAP-310;    -   anti-Mesothelin antibodies, such as SEL-403;    -   Thymidine kinase stimulators, such as aglatimagene besadenovec;    -   Polo-like kinase 1 inhibitors, such as PCM-075, onvansertib;    -   NAE inhibitors, such as pevonedistat (MLN-4924), TAS-4464;        Pleiotropic pathway modulators, such as avadomide (CC-122);    -   Amyloid protein binding protein-1 inhibitorS/Ubiquitin ligase        modulators, such as pevonedistat;    -   FoxM1 inhibitors, such as thiostrepton;    -   UBA1 inhibitors, such as TAK-243;    -   Src tyrosine kinase inhibitors, such as VAL-201;    -   VDAC/HK inhibitors, such as VDA-1102;    -   Elf4a inhibitors, such as rohinitib, eFT226;    -   TP53 gene stimulators, such as ad-p53;    -   Retinoic acid receptor agonists, such as tretinoin;    -   Retinoic acid receptor alpha (RARα) inhibitors, such as SY-1425;    -   SIRT3 inhibitors, such as YC8-02;    -   Stromal cell-derived factor 1 ligand inhibitors, such as        olaptesed pegol (NOX-A12);    -   IL-4 receptor modulators, such as MDNA-55;    -   Arginase-I stimulators, such as pegzilarginase;    -   Topoisomerase I inhibitors, such as irinotecan hydrochloride,        Onivyde;    -   Topoisomerase I inhibitor/hypoxia inducible factor-1 alpha        inhibitors, such as PEG-SN38 (firtecan pegol);    -   Hypoxia inducible factor-1 alpha inhibitors, such as PT-2977,        PT-2385;    -   CD122 (IL-2 receptor) agonists, such as proleukin (aldesleukin,        IL-2); pegylated IL-2 (eg NKTR-214); modified variants of IL-2        (eg THOR-707);    -   TLR7/TLR8 agonist, such as NKTR-262;    -   TLR7 agonists, such as DS-0509, GS-9620, LHC-165, TMX-101        (imiquimod);    -   p53 tumor suppressor protein stimulators such as kevetrin;    -   Mdm4/Mdm2 p53-binding protein inhibitors, such as ALRN-6924;    -   kinesin spindle protein (KSP) inhibitors, such as filanesib        (ARRY-520);    -   CD80-fc fusion protein inhibitors, such as FPT-155;    -   Menin and mixed lineage leukemia (MLL) inhibitors such as        KO-539;    -   Liver x receptor agonists, such as RGX-104;    -   IL-10 agonists, such as Pegilodecakin (AM-0010);    -   VEGFR/PDGFR inhibitors, such as vorolanib;    -   IRAK4 inhibitors, such as CA-4948;    -   anti-TLR-2 antibodies, such as OPN-305;    -   Calmodulin modulators, such as CBP-501;    -   Glucocorticoid receptor antagonists, such as relacorilant        (CORT-125134);    -   Second mitochondria-derived activator of caspases (SMAC) protein        inhibitors, such as BI-891065;    -   Lactoferrin modulators, such as LTX-315;    -   KIT proto-oncogene, receptor tyrosine kinase (KIT) inhibitors,        such as PLX-9486;    -   platelet derived growth factor receptor alpha (PDGFRA)/KIT        proto-oncogene, receptor tyrosine kinase (KIT) mutant-specific        antagonists/inhibitors such as BLU-285, DCC-2618;    -   Exportin 1 inhibitors, such as eltanexor;    -   CHST15 gene inhibitors, such as STNM-01;    -   Somatostatin receptor antagonist, such as OPS-201;    -   CEBPA gene stimulators, such as MTL-501;    -   DKK3 gene modulators, such as MTG-201;    -   Chemokine (CXCR1/CXCR2) inhibitors, such as SX-682;    -   p70s6k inhibitors, such as MSC2363318A;    -   methionine aminopeptidase 2 (MetAP2) inhibitors, such as M8891,        APL-1202;    -   arginine N-methyltransferase 5 inhibitors, such as GSK-3326595;    -   CD71 modulators, such as CX-2029 (ABBV-2029);    -   ATM (ataxia telangiectasia) inhibitors, such as AZD0156,        AZD1390;    -   CHK1 inhibitors, such as GDC-0575, LY2606368 (prexasertib),        SRA737, RG7741 (CHK1/2);    -   CXCR4 antagonists, such as BL-8040, LY2510924, burixafor        (TG-0054), X4P-002, X4P-00140, Plerixafor;    -   EXH2 inhibitors, such as GSK2816126;    -   KDM1 inhibitors, such as ORY-1001, IMG-7289, INCB-59872,        GSK-2879552;    -   CXCR2 antagonists, such as AZD-5069;    -   GM-CSF antibodies, such as lenzilumab;    -   DNA dependent protein kinase inhibitors, such as MSC2490484A        (nedisertib), VX-984, AsiDNA (DT-01); protein kinase C (PKC)        inhibitors, such as LXS-196, sotrastaurin;    -   Selective estrogen receptor downregulators (SERD), such as        fulvestrant (Faslodex®), RG6046, RG6047, RG6171, elacestrant        (RAD-1901), SAR439859 and AZD9496;    -   Selective estrogen receptor covalent antagonists (SERCAs), such        as H3B-6545;    -   selective androgen receptor modulator (SARM), such as GTX-024,        darolutamide;    -   transforming growth factor-beta (TGF-beta) kinase antagonists,        such as galunisertib, LY3200882; TGF-beta inhibitors described        in WO 2019/103203;    -   TGF beta receptor 1 inhibitors, such as PF-06952229;    -   bispecific antibodies, such as ABT-165 (DLL4/VEGF), MM-141        (IGF-1/ErbB3), MM-111 (Erb2/Erb3), JNJ-64052781 (CD19/CD3),        PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A), JNJ-61186372        (EGFR/cMET), AMG-211 (CEA/CD3), RG7802 (CEA/CD3), ERY-974        (CD3/GPC3) vancizumab (angiopoietins/VEGF), PF-06671008        (Cadherins/CD3), AFM-13 (CD16/CD30), APV0436 (CD123/CD3),        flotetuzumab (CD123/CD3), REGN-1979 (CD20/CD3), MCLA-117        (CD3/CLEC12A), MCLA-128 (HER2/HER3), JNJ-0819, JNJ-7564        (CD3/heme), AMG-757 (DLL3-CD3), MGD-013 (PD-1/LAG-3), FS-118        (LAG-3/PD-L1) MGD-019 (PD-1/CTLA-4), KN-046 (PD-1/CTLA-4),        MEDI-5752 (CTLA-4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717        (PD-1/CTLA-4), AK-104 (CTLA-4/PD-1), AMG-330 (CD33/CD3), AMG-420        (BCMA/CD3), BI-836880 (VEFG/ANG2), JNJ-63709178 (CD123/CD3),        MGD-007 (CD3/gpA33), MGD-009 (CD3/B7H3), AGEN1223, IMCgp100        (CD3/gp100), AGEN-1423, ATOR-1015 (CTLA-4/OX40), LY-3415244        (TIM-3/PDL1), INHIBRX-105 (4-1BB/PDL1), faricimab        (VEGF-A/ANG-2), FAP-4-IBBL (4-1BB/FAP), XmAb-13676 (CD3/CD20),        TAK-252 (PD-1/OX40L), TG-1801 (CD19/CD47), XmAb-18087        (SSTR2/CD3), catumaxomab (CD3/EpCAM), SAR-156597 (IL4/IL13),        EMB-01 (EGFR/cMET), REGN-4018 (MUC16/CD3), REGN-1979 (CD20/CD3),        RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458 (CD3/BCMA),        navicixizumab (DLL4/VEGF), GRB-1302 (CD3/Erbb2), vanucizumab        (VEGF-A/ANG-2), GRB-1342 (CD38/CD3), GEM-333 (CD3/CD33),        IMM-0306 (CD47/CD20), RG6076, MEDI5752 (PD-1/CTLA-4), LY3164530        (MET/EGFR);    -   Alpha-ketoglutarate dehydrogenase (KGDH) inhibitors, such as        CPI-613;    -   XPO₁ inhibitors, such as selinexor (KPT-330);    -   Isocitrate dehydrogenase 2 (IDH2) inhibitors, such as enasidenib        (AG-221);    -   IDH1 inhibitors such as AG-120, and AG-881 (IDH1 and IDH2),        IDH-305, BAY-1436032;    -   IDH1 gene inhibitors, such as ivosidenib;    -   interleukin-3 receptor (IL-3R) modulators, such as SL-401;    -   Arginine deiminase stimulators, such as pegargiminase        (ADI-PEG-20);    -   claudin-18 inhibitors, such as claudiximab;    -   f3-catenin inhibitors, such as CWP-291;    -   chemokine receptor 2 (CCR) inhibitors, such as PF-04136309,        CCX-872, BMS-813160 (CCR2/CCR5);    -   thymidylate synthase inhibitors, such as ONX-0801;    -   ALK/ROS1 inhibtors, such as lorlatinib;    -   tankyrase inhibitors, such as G007-LK;    -   Mdm2 p53-binding protein inhibitors, such as CMG-097, HDM-201;        c-PIM inhibitors, such as PIM447;    -   sphingosine kinase-2 (SK2) inhibitors, such as Yeliva®        (ABC294640);    -   DNA polymerase inhibitors, such as sapacitabine;    -   Cell cycle/Microtubule inhibitors, such as eribulin mesylate;    -   c-MET inhibitors, such as AMG-337, savolitinib, tivantinib        (ARQ-197), capmatinib, and tepotinib, ABT-700, AG213, AMG-208,        JNJ-38877618 (0M0-1), merestinib, HQP-8361;    -   c-Met/VEGFR inhibitors, such as BMS-817378, TAS-115;    -   c-Met/RON inhibitors, such as BMS-777607;    -   BCR/ABL inhibitors, such as rebastinib, asciminib, ponatinib        (ICLUSIG®);    -   MNK1/MNK2 inhibitors, such as eFT-508;    -   Cytochrome P450 11B2/Cytochrome P450 17/AKT protein kinase        inhibitors, such as LAE-201;    -   Cytochrome P450 3A4 stimulators, such as mitotane;    -   lysine-specific demethylase-1 (LSD1) inhibitors, such as        CC-90011;    -   CSF1R/KIT and FLT3 inhibitors, such as pexidartinib (PLX3397);    -   Flt3 tyrosine kinase/Kit tyrosine kinase inhibitor and PDGF        receptor antagonists, such as quizartinib dihydrochloride;    -   kinase inhibitors, such as vandetanib;    -   E selectin antagonists, such as GMI-1271;    -   differentiation inducers, such as tretinoin;    -   epidermal growth factor receptor (EGFR) inhibitors, such as        osimertinib (AZD-9291), cetuximab;    -   topoisomerase inhibitors, such as Adriamycin, doxorubicin,        daunorubicin, dactinomycin, DaunoXome, Caelyx, eniposide,        epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone,        pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal        irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67,        mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven        (MGI-114);    -   corticosteroids, such as cortisone, dexamethasone,        hydrocortisone, methylprednisolone, prednisone, prednisolone;    -   growth factor signal transduction kinase inhibitors;    -   nucleoside analogs, such as DFP-10917;    -   Ax1 inhibitors, such as BGB-324 (bemcentinib), SLC-0211;    -   Ax1/Flt3 inhibitors, such as gilteritinib;    -   Inhibitors of bromodomain and extraterminal motif (BET)        proteins, including ABBV-744, BRD2 (NCBI Gene ID: 6046), BRD3        (NCBI Gene ID: 8019), BRD4 (NCBI Gene ID: 23476), and        bromodomain testis-specific protein (BRDT; NCBI Gene ID: 676),        such as INCB-054329, INCB057643, TEN-010, AZD-5153, ABT-767,        BMS-986158, CC-90010, GSK525762 (molibresib), NHWD-870, ODM-207,        GSK-2820151, GSK-1210151A, ZBC246, ZBC260, ZEN3694, FT-1101,        RG-6146, CC-90010, CC-95775, mivebresib, BI-894999, PLX-2853,        PLX-51107, CPI-0610, GS-5829;    -   PARP inhibitors, such as olaparib (MK7339), rucaparib,        veliparib, talazoparib, ABT-767, BGB-290, fluzolepali        (SHR-3162), niraparib (JNJ-64091742), bendamustine        hydrochloride,    -   PARP/Tankyrase inhibitors such as 2X-121 (e-7499);    -   IMP-4297, SC-10914, IDX-1197, HWH-340, CK-102, simmiparib;    -   Proteasome inhibitors, such as ixazomib (NINLARO®), carfilzomib        (Kyprolis®), marizomib, bortezomib;    -   Glutaminase inhibitors, such as CB-839 (telaglenastat),        bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide        (BPTES);    -   mitochondrial complex I inhibitors, such as metformin,        phenformin;    -   Vaccines, such as peptide vaccine TG-01 (RAS), GALE-301,        GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410,        VXL-100, DPX-E7, ISA-101, 6MHP, OSE-2101, galinpepimut-S,        SVN53-67/M57-KLH, IMU-131, peptide subunit vaccine (acute        lymphoblastic leukemia, University Children's Hospital        Tuebingen); bacterial vector vaccines such as CRS-207/GVAX,        axalimogene filolisbac (ADXS11-001); adenovirus vector vaccines        such as nadofaragene firadenovec; autologous Gp96 vaccine;        dendritic cells vaccines, such as CVactm, tapuldencel-T,        eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003),        DCVAC, CVactm, stapuldencel-T, eltrapuldencel-T, SL-701,        BSK01TM, ADXS31-142, autologous dendritic cell vaccine        (metastatic malignant melanoma, intradermal/intravenous,        Universitatsklinikum Erlangen); oncolytic vaccines such as,        talimogene laherparepvec, pexastimogene devacirepvec, GL-ONC1,        MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3,        ASN-002 (TG-1042); therapeutic vaccines, such as CVAC-301,        CMP-001, CreaVax-BC, PF-06753512, VBI-1901, TG-4010, ProscaVax™;        tumor cell vaccines, such as Vigil® (IND-14205), Oncoquest-L        vaccine; live attenuated, recombinant, serotype 1 poliovirus        vaccine, such as PVS-RIPO; Adagloxad simolenin; MEDI-0457;        DPV-001 a tumor-derived, autophagosome enriched cancer vaccine;        RNA vaccines such as, CV-9209, LV-305; DNA vaccines, such as        MEDI-0457, MVI-816, INO-5401; modified vaccinia virus Ankara        vaccine expressing p53, such as MVA-p53; DPX-Survivac; BriaVax™;        GI-6301; GI-6207; GI-4000; 10-103; Neoantigen peptide vaccines,        such as AGEN-2017, GEN-010, NeoVax, RG-6180, GEN-009, PGV-001        (TLR-3 agonist), GRANITE-001, NEO-PV-01; Peptide vaccines that        target heat shock proteins, such as PhosphoSynVax™; Vitespen        (HSPPC-96-C), NANT Colorectal Cancer Vaccine containing        aldoxorubicin, autologous tumor cell vaccine+systemic        CpG-B+IFN-alpha (cancer), 10-120+10-103 (PD-L1/PD-L2 vaccines),        HB-201, HB-202, HB-301, TheraT®*-based vaccines;    -   TLR-3 agonist/interferon inducers, such as Poly-ICLC        (NSC-301463);    -   STAT-3 inhibitors, such as napabucasin (BBI-608); ATPase p97        inhibitors, such as CB-5083;    -   smoothened (SMO) receptor inhibitors, such as Odomzo®        (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449),        BMS-833923, glasdegib (PF-04449913), LY2940680, and        itraconazole;    -   interferon alpha ligand modulators, such as interferon alpha-2b,        interferon alpha-2a biosimilar (Biogenomics), ropeginterferon        alfa-2b (AOP-2014, P-1101, PEG IFN alpha-2b), Multiferon        (Alfanative, Viragen), interferon alpha 1b, Roferon-A (Canferon,        Ro-25-3036), interferon alfa-2a follow-on biologic        (Biosidus)(Inmutag, Inter 2A), interferon alfa-2b follow-on        biologic (Biosidus—Bioferon, Citopheron, Ganapar, Beijing Kawin        Technology—Kaferon), Alfaferone, pegylated interferon alpha-lb,        peginterferon alfa-2b follow-on biologic (Amega), recombinant        human interferon alpha-lb, recombinant human interferon        alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN        alpha 2b conjugate, Dynavax (SD-101), and interferon alfa-n1        (Humoferon, SM-10500, Sumiferon);    -   interferon gamma ligand modulators, such as interferon gamma        (OH-6000, Ogamma 100);    -   IL-6 receptor modulators, such as tocilizumab, AS-101 (CB-06-02,        IVX-Q-101);    -   Heat shock protein inhibitors/IL-6 receptor antagonists, such as        siltuximab;    -   Telomerase modulators, such as, tertomotide (GV-1001, HR-2802,        Riavax) and imetelstat (GRN-163, JNJ-63935937);    -   DNA methyltransferases inhibitors, such as temozolomide        (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110),        KRX-0402, RX-3117, RRx-001, and azacytidine (CC-486);    -   DNA gyrase inhibitors, such as pixantrone and sobuzoxane; DNA        gyrase inhibitors/Topoisimerase II inhibitors, such as        amrubicin;    -   Bcl-2 family protein inhibitors, such as ABT-263, venetoclax        (ABT-199), ABT-737, RG7601, and AT-101;    -   Bcl-2/Bcl-XL inhibitors, such as novitoclax;    -   Notch inhibitors, such as LY3039478 (crenigacestat), tarextumab        (anti-Notch2/3), BMS-906024;    -   hyaluronidase stimulators, such as PEGPH-20;    -   Erbb2 tyrosine kinase receptor inhibitors/Hyaluronidase        stimulators, such as Herceptin Hylecta;    -   Wnt pathway inhibitors, such as SM-04755, PRI-724, WNT-974;    -   gamma-secretase inhibitors, such as PF-03084014, MK-0752,        RO-4929097;    -   Grb-2 (growth factor receptor bound protein-2) inhibitors, such        as BP1001;    -   TRAIL pathway-inducing compounds, such as ONC201, ABBV-621;    -   TRAIL modulators, such as SCB-313;    -   Focal adhesion kinase inhibitors, such as VS-4718, defactinib,        GSK2256098;    -   hedgehog inhibitors, such as saridegib, sonidegib (LDE225),        glasdegib;    -   Aurora kinase inhibitors, such as alisertib (MLN-8237), and        AZD-2811, AMG-900, barasertib, ENMD-2076;    -   HSPB1 modulators (heat shock protein 27, HSP27), such as        brivudine, apatorsen;    -   ATR inhibitors, such as BAY-937, AZD6738, AZD6783, VX-803,        VX-970 (berzosertib) and VX-970;    -   Hsp90 inhibitors, such as AUY922, onalespib (AT13387), SNX-2112,        SNX5422;    -   Murine double minute (mdm2) oncogene inhibitors, such as        DS-3032b, RG7775, AMG-232, HDM201, and idasanutlin (RG7388);    -   CD137 agonists, such as urelumab, utomilumab (PF-05082566),        AGEN2373, ADG-106, BT-7480;    -   STING agonists, such as ADU-S100 (MIW-815), SB-11285, MK-1454,        SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291,        GSK3745417;    -   FGFR inhibitors, such as FGF-401, INCB-054828, BAY-1163877,        AZD4547, JNJ-42756493, LY2874455, Debio-1347;    -   fatty acid synthase (FASN) inhibitors, such as TVB-2640;    -   Antigen CD19 inhibitors, such as MOR208, MEDI-551, AFM-11,        inebilizumab;    -   CD44 binders, such as A6;    -   protein phosphatease 2A (PP2A) inhibitors, such as LB-100;    -   CYP17 inhibitors, such as seviteronel (VT-464), ASN-001,        ODM-204, CFG920, abiraterone acetate;    -   RXR agonists, such as IRX4204;    -   hedgehog/smoothened (hh/Smo) antagonists, such as taladegib,        patidegib, vismodegib;    -   complement C3 modulators, such as Imprime PGG;    -   IL-15 agonists, such as ALT-803, NKTR-255, interleukin-15/Fc        fusion protein, AM-0015, NIZ-985, and hetlL-15;    -   EZH2 (enhancer of zeste homolog 2) inhibitors, such as        tazemetostat, CPI-1205, GSK-2816126, PF-06821497;    -   Oncolytic viruses, such as pelareorep, CG-0070, MV-NIS therapy,        HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev        (DNX-2401), vocimagene amiretrorepvec, RP-1, CVA21, Celyvir,        LOAd-703, OBP-301, IMLYGIC®;    -   DOT1L (histone methyltransferase) inhibitors, such as        pinometostat (EPZ-5676);    -   toxins such as Cholera toxin, ricin, Pseudomonas exotoxin,        Bordetella pertussis adenylate cyclase toxin, diphtheria toxin,        and caspase activators;    -   DNA plasmids, such as BC-819;    -   PLK inhibitors of PLK 1, 2, and 3, such as volasertib (PLK1);    -   WEE1 inhibitors, such as AZD-1775 (adavosertib); Rho kinase        (ROCK) inhibitors, such as AT13148, KD025;    -   Inhibition of Apoptosis Protein (IAP) inhibitors, such as        ASTX660, debio-1143, birinapant, APG-1387, LCL-161;    -   RNA polymerase inhibitors, such has lurbinectedin (PM-1183),        CX-5461; Tubulin inhibitors, such as PM-184, BAL-101553        (lisavanbulin), and OXI-4503,    -   fluorapacin (AC-0001), plinabulin, vinflunine;    -   Toll-like receptor 4 (TLR-4) agonists, such as G100, GSK1795091,        and PEPA-10;    -   Elongation factor 1 alpha 2 inhibitors, such as plitidepsin;    -   Elongation factor 2 inhibitors/Interleukin-2 ligands/NAD ADP        ribosyltransferase stimulators, such as denileukin diftitox;    -   CD95 inhibitors, such as APG-101, APO-010, asunercept;    -   WT1 inhibitors, such as DSP-7888;    -   splicing factor 3B subunitl (SF3B1) inhibitors, such as H3B-8800    -   retinoid Z receptor gamma (RORy) agonists, such as LYC-55716;        and Microbiome modulators, such as SER-401, EDP-1503, MRx-0518.

In some embodiments, a compound as described herein, is co-administeredwith one or more additional therapeutic agents comprising an inhibitoror antagonist of: myeloid cell leukemia sequence 1 (MCL1) apoptosisregulator (NCBI Gene ID: 4170); mitogen-activated protein kinase 1(MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1), NCBIGene ID: 11184); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 orDGK-alpha; NCBI Gene ID: 1606); 5′-nucleotidase ecto (NT5E or CD73; NCBIGene ID: 4907); ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1or CD39; NCBI Gene ID: 593); transforming growth factor beta 1 (TGFB1 orTG93; NCBI Gene ID: 7040); heme oxygenase 1 (HMOX1, HO-1 or H01; NCBIGene ID: 3162); heme oxygenase 2 (HMOX2, HO-2 or HO2; NCBI Gene ID:3163); vascular endothelial growth factor A (VEGFA or VEGF; NCBI GeneID: 7422); erb-b2 receptor tyrosine kinase 2 (ERBB2, HER², HER2/neu orCD340; NCBI Gene ID: 2064), epidermal growth factor receptor (EGFR,ERBB, ERBB1 or HER1; NCBI Gene ID: 1956); ALK receptor tyrosine kinase(ALK, CD246; NCBI Gene ID: 238); poly(ADP-ribose) polymerase 1 (PARP1;NCBI Gene ID: 142); poly(ADP-ribose) polymerase 2 (PARP2; NCBI Gene ID:10038); TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PARP7; NCBIGene ID: 25976); cyclin dependent kinase 4 (CDK4; NCBI Gene ID: 1019);cyclin dependent kinase 6 (CDK6; NCBI Gene ID: 1021); TNF receptorsuperfamily member 14 (TNFRSF14, HVEM, CD270; NCBI Gene ID: 8764); Tcell immunoreceptor with Ig and ITIM domains (TIGIT; NCBI Gene ID:201633); X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3; NCBI GeneID: 331); baculoviral IAP repeat containing 2 (BIRC2, cIAP1; NCBI GeneID: 329); baculoviral IAP repeat containing 3 (BIRC3, cIAP2; NCBI GeneID: 330); baculoviral IAP repeat containing 5 (BIRC5, surviving; NCBIGene ID: 332); C—C motif chemokine receptor 2 (CCR², CD192; NCBI GeneID: 729230); C—C motif chemokine receptor 5 (CCR5, CD195; NCBI Gene ID:1234); C—C motif chemokine receptor 8 (CCR8, CDw198; NCBI Gene ID:1237); C—X—C motif chemokine receptor 2 (CXCR², CD182; NCBI Gene ID:3579); C—X—C motif chemokine receptor 3 (CXCR3, CD182, CD183; NCBI GeneID: 2833); C—X—C motif chemokine receptor 4 (CXCR4, CD184; NCBI Gene ID:7852); arginase (ARG1 (NCBI Gene ID: 383), ARG2 (NCBI Gene ID: 384)),carbonic anhydrase (CA1 (NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760),CA3 (NCBI Gene ID: 761), CA4 (NCBI Gene ID: 762), CASA (NCBI Gene ID:763), CASB (NCBI Gene ID: 11238), CA6 (NCBI Gene ID: 765), CA7 (NCBIGene ID: 766), CA8 (NCBI Gene ID: 767), CA9 (NCBI Gene ID: 768), CA10(NCBI Gene ID: 56934), CA11 (NCBI Gene ID: 770), CA12 (NCBI Gene ID:771), CA13 (NCBI Gene ID: 377677), CA14 (NCBI Gene ID: 23632)),prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1; NCBI Gene ID:5742), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI GeneID: 5743), secreted phospholipase A2, prostaglandin E synthase (PTGES,PGES; Gene ID: 9536), arachidonate 5-lipoxygenase (ALOXS, 5-LOX; NCBIGene ID: 240) and/or soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI GeneID: 2053); a secreted phospholipase A2 (e.g., PLA2G1B (NCBI Gene ID:5319); PLA2G7 (NCBI Gene ID: 7941), PLA2G3 (NCBI Gene ID: 50487),PLA2G2A (NCBI Gene ID: 5320); PLA2G4A (NCBI Gene ID: 5321); PLA2G12A(NCBI Gene ID: 81579); PLA2G12B (NCBI Gene ID: 84647); PLA2G10 (NCBIGene ID: 8399); PLA2G5 (NCBI Gene ID: 5322); PLA2G2D (NCBI Gene ID:26279); PLA2G15 (NCBI Gene ID: 23659)); indoleamine 2,3-dioxygenase 1(IDO1; NCBI Gene ID: 3620); indoleamine 2,3-dioxygenase 2 (IDO2; NCBIGene ID: 169355); hypoxia inducible factor 1 subunit alpha (HIF1A; NCBIGene ID: 3091); angiopoietin 1 (ANGPT1; NCBI Gene ID: 284); EndothelialTEK tyrosine kinase (TIE-2, TEK, CD202B; NCBI Gene ID: 7010); Januskinase 1 (JAK1; NCBI Gene ID: 3716); catenin beta 1 (CTNNB1; NCBI GeneID: 1499); histone deacetylase 9 (HDAC9; NCBI Gene ID: 9734) and/or5′-3′ exoribonuclease 1 (XRN1; NCBI Gene ID: 54464).

TCR Signaling Modulators

In various embodiments, a compound as described herein, is combined withone or more agonist or antagonist of T-Cell Receptor (TCR) signalingmodulators. Activation of T cells through the TCR and is essential forthymocyte development and effector T cell function. TCR activationpromotes signaling cascades that ultimately determine cell fate throughregulating cytokine production, cell survival, proliferation, anddifferentiation. Examples of TCR signaling modulators include withoutlimitation CD2 (cluster of differentiation 2, LFA-2, T11, LFA-3receptor), CD3 (cluster of differentiation 3), CD4 (cluster ofdifferentiation 4), CD8 (cluster of differentiation 8), CD28 (cluster ofdifferentiation 28), CD45 (PTPRC, B220, GP180), LAT (Linker foractivation of T cells, LAT1), Lck, LFA-1 (ITGB2, CD18, LAD, LCAMB), Src,Zap-70, SLP-76, DGKalpha, CBL-b, CISH, HPK1.

Examples of agonist of cluster of differentiation 3 (CD3) that can beco-administered include without limitation MGD015.

In various embodiments, a compound as described herein, is combined withone or more blockers or inhibitors of inhibitory immune checkpointproteins or receptors and/or with one or more stimulators, activators oragonists of one or more stimulatory immune checkpoint proteins orreceptors. Blockade or inhibition of inhibitory immune checkpoints canpositively regulate T-cell or NK cell activation and prevent immuneescape of cancer cells within the tumor microenvironment. Activation orstimulation of stimulatory immune check points can augment the effect ofimmune checkpoint inhibitors in cancer therapeutics. In variousembodiments, the immune checkpoint proteins or receptors regulate T cellresponses (e.g., reviewed in Xu, et al., J Exp Clin Cancer Res. (2018)37:110). In various embodiments, the immune checkpoint proteins orreceptors regulate NK cell responses (e.g., reviewed in Davis, et al.,Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol.(2018) 18(11):671-688).

Examples of immune checkpoint proteins or receptors include withoutlimitation CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembraneand immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B,SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-setdomain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-setimmunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulinsuperfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicityreceptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2,B7H7); inducible T cell costimulator (ICOS, CD278); inducible T cellcostimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4(TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8(CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9(CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10(TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and Tlymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF);TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-relatedsequence A (MICA); MHC class I polypeptide-related sequence B (MICB);CD274 (PDL1, PD-L1); programmed cell death 1 (PDCD1, PD-1, PD-1);cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1),CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1);Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155); PVRrelated immunoglobulin domain containing (PVRIG, CD112R); T cellimmunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulinand mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellularreceptor 2 (HAVCR², TIMD3, TIM-3); galectin 9 (LGALS9); lymphocyteactivating 3 (LAG-3, CD223); signaling lymphocytic activation moleculefamily member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229,SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7(SLAMF7, CD319); UL16 binding protein 1 (ULBP1); UL16 binding protein 2(ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcriptlE (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5);retinoic acid early transcript 1L (RAET1L; ULBP6); lymphocyte activating3 (CD223); killer cell immunoglobulin like receptor (KIR); killer celllectin like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin likereceptor K1 (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2(KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3,NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cellimmunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1(KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains andlong cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin likereceptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killercell immunoglobulin like receptor, three Ig domains and long cytoplasmictail 1 (KIR3DL1); killer cell lectin like receptor D1 (KLRD1).

In various embodiments, a compound as described herein, is combined withone or more blockers or inhibitors of one or more T-cell inhibitoryimmune checkpoint proteins or receptors. Illustrative T-cell inhibitoryimmune checkpoint proteins or receptors include without limitation CD274(PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2,CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxicT-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-setdomain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-setimmunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulinsuperfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14(HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR relatedimmunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptorwith Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG-3,CD223); hepatitis A virus cellular receptor 2 (HAVCR², TIMD3, TIM-3);galectin 9 (LGALS9); killer cell immunoglobulin like receptor (KIR);killer cell immunoglobulin like receptor, two Ig domains and longcytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor,two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cellimmunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3(KIR2DL3); and killer cell immunoglobulin like receptor, three Igdomains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, acompound as described herein, is combined with one or more agonist oractivators of one or more T-cell stimulatory immune checkpoint proteinsor receptors. Illustrative T-cell stimulatory immune checkpoint proteinsor receptors include without limitation CD27, CD70; CD40, CD40LG;inducible T cell costimulator (ICOS, CD278); inducible T cellcostimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4(TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9(CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1),CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1);CD244 (2B4, SLAMF4), Poliovirus receptor (PVR) cell adhesion molecule(PVR, CD155). See, e.g., Xu, et al., J Exp Clin Cancer Res. (2018)37:110.

In various embodiments, a compound as described herein, is combined withone or more blockers or inhibitors of one or more NK-cell inhibitoryimmune checkpoint proteins or receptors. Illustrative NK-cell inhibitoryimmune checkpoint proteins or receptors include without limitationkiller cell immunoglobulin like receptor, three Ig domains and longcytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin likereceptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killercell immunoglobulin like receptor, two Ig domains and long cytoplasmictail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Igdomains and long cytoplasmic tail 3 (KIR2DL3); killer cellimmunoglobulin like receptor, three Ig domains and long cytoplasmic tail1 (KIR3DL1); killer cell lectin like receptor C1 (KLRC1, NKG2A, CD159A);and killer cell lectin like receptor D1 (KLRD1, CD94). In variousembodiments, a compound as described herein, is combined with one ormore agonist or activators of one or more NK-cell stimulatory immunecheckpoint proteins or receptors. Illustrative NK-cell stimulatoryimmune checkpoint proteins or receptors include without limitation CD16,CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin like receptor K1(KLRK1, NKG2D, CD314); SLAM family member 7 (SLAMF7). See, e.g., Davis,et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol.(2017) 31:37-54; and Chiossone, et al., Nat Rev Immunol. (2018)18(11):671-688.

In various embodiments, a compound as described herein, is combined withan inhibitor of CD47 (IAP, MER6, 0A3; NCBI Gene ID: 961). Examples ofCD47 inhibitors include without limitation to anti-CD47 mAbs (Vx-1004),anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanizedanti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, ALX-148,TTI-621, RRx-001, DSP-107, VT-1021, TTI-621, TTI-622, IMM-02 SGN-CD47M.Examples bi-specific antibodies targeting CD47, such as IBI-322(CD47/PD-L1), IMM-0306 (CD47/CD20), TJ-L1C4 (CD47/PD-L1), HX-009(CD47/PD-1), PMC-122 (CD47/PD-L1), PT-217, (CD47/DLL3), IMM-26011(CD47/FLT3), IMM-0207 (CD47/VEGF), IMM-2902 (CD47/HER2), BH29xx(CD47/PD-L1), IMM-03 (CD47/CD20), IMM-2502 (CD47/PD-L1), HMBD-004B(CD47/BCMA), HMBD-004A (CD47/CD33). Examples of anti-CD47antibodies,such as IBI-188, TJC-4, SHR-1603, HLX-24, LQ-001, IMC-002, ZL-1201,IMM-01, B6H12, GenSci-059, TAY-018, PT-240, 1F8-GMCSF, SY-102, KD-015

In some embodiments, the one or more immune checkpoint inhibitorscomprises a proteinaceous (e.g., antibody or fragment thereof, orantibody mimetic) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. Insome embodiments, the one or more immune checkpoint inhibitors comprisesa small organic molecule inhibitor of PD-L1 (CD274), PD-1 (PDCD1) orCTLA4.

Examples of inhibitors of CTLA4 that can be co-administered includewithout limitation ipilimumab, tremelimumab, BMS-986218, AGEN1181,AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145,APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161,ATOR-1144, PBI-5D3H5, BPI-002, HBM-4003, as well as multi-specificinhibitors FPT-155 (CTLA4/PD-L1/CD28), PF-06936308 (PD-1/CTLA4), MGD-019(PD-1/CTLA4), KN-046 (PD-1/CTLA4), MEDI-5752 (CTLA4/PD-1), XmAb-20717(PD-1/CTLA4), and AK-104 (CTLA4/PD-1).

Examples of inhibitors/antibodies of PD-L1 (CD274) or PD-1 (PDCD1) thatcan be co-administered include without limitation pembrolizumab,nivolumab, cemiplimab, pidilizumab, AMG-404, AMP-224, MEDI0680(AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab,BMS-936559, CK-301, PF-06801591, BGB-A317 (tislelizumab), GEN-1046(PD-L1/4-1BB), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003,HLX-10, MGA-012, BI-754091, AGEN-2034, JS-001 (toripalimab),JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100, LY-3300054,SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181, PD1-PIK, BAT-1306,(MSB0010718C), CX-072, CBT-502, TSR-042 (dostarlimab), MSB-2311,JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308(sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135,FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181,as well as multi-specific inhibitors FPT-155 (CTLA4/PD-L1/CD28),PF-06936308 (PD-1/CTLA4), MGD-013 (PD-1/LAG-3), RO-7247669 (PD-1/LAG-3),FS-118 (LAG-3/PD-L1) MGD-019 (PD-1/CTLA4), KN-046 (PD-1/CTLA4),MEDI-5752 (CTLA4/PD-1), RO-7121661 (PD-1/TIM-3), XmAb-20717(PD-1/CTLA4), AK-104 (CTLA4/PD-1), M7824 (PD-L1/TGFβ-EC domain), CA-170(PD-L1/VISTA), CDX-527 (CD27/PD-L1), LY-3415244 (TIM-3/PDL1), RG7769(PD-1/TIM-3) and INBRX-105 (4-1BB/PDL1), GNS-1480 (PD-L1/EGFR), RG-7446(Tecentriq, atezolizumab), ABBV-181, nivolumab (OPDIVO®, BMS-936558,MDX-1106), pembrolizumab (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab,CAS Reg. No. 1374853-91-4), pidilizumab, PF-06801591, BGB-A317(tislelizumab), GLS-010 (WBP-3055), AK-103 (HX-008), CS-1003, HLX-10,MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN-2034, JS-001(toripalimab), JNJ-63723283, genolimzumab (CBT-501), LZM-009, BCD-100,LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181,AK-105, PD1-PIK, BAT-1306, BMS-936559, atezolizumab (MPDL3280A),durvalumab (MEDI-4736), avelumab, CK-301, (MSB0010718C), MEDI-0680,CX-072, CBT-502, PDR-001 (spartalizumab), PDR001+Tafinlar®+Mekinist®,MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035,IBI-308 (sintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001),BCD-135, FAZ-053, TQB-2450, and MDX1105-01.

Examples of inhibitors of PVRIG that can be co-administered includewithout limitation: COM-701.

Examples of inhibitors of TIGIT that can be co-administered includewithout limitation: BMS-986207, RG-6058, AGEN-1307, COM-902.

Examples of inhibitors of TIM-3 that can be co-administered includewithout limitation: TSR-022, LY-3321367, MBG-453, INCAGN-2390,RO-7121661 (PD-1/TIM-3), LY-3415244 (TIM-3/PDL1), RG7769 (PD-1/TIM-3).

Examples of inhibitors of LAG-3 that can be co-administered includewithout limitation: relatlimab (ONO-4482), LAG-525, MK-4280, REGN-3767,INCAGN2385, TSR-033, MGD-013 (PD-1/LAG-3), FS-118 (LAG-3/PD-L1).

Examples of anti-killer cell immunoglobulin like receptor, three Igdomains and long cytoplasmic tail 1 (KIR3DL1; KIR; NCBI Gene ID: 3811)monoclonal antibodies, such as lirilumab (IPH-2102), IPH-4102.

Examples of anti-NKG2a antibodies that can be co-administered includewithout limitation: monalizumab.

Examples of anti-VISTA antibodies that can be co-administered includewithout limitation: HMBD-002, CA-170 (PD-L1/VISTA).

Examples of anti-CD70 antibodies that can be co-administered includewithout limitation: AMG-172.

Examples of anti-CD20 antibodies that can be co-administered includewithout limitation: obinutuzumab, IGN-002, PF-05280586.

Examples of anti-ICOS antibodies that can be co-administered includewithout limitation: JTX-2011, GSK3359609.

Examples of ICOS agonists that can be co-administered include withoutlimitation: ICOS-L.COMP (Gariepy, J. et al. 106th Annu Meet Am AssocImmunologists (AAI) (May 9-13, San Diego) 2019, Abst 71.5).

TNF Receptor Superfamily (TNFRSF) Member Agonists or Activators

In various embodiments, a compound as described herein, is combined withan agonist of one or more TNF receptor superfamily (TNFRSF) members,e.g., an agonist of one or more of TNFRSF1A (NCBI Gene ID: 7132),TNFRSF1B (NCBI Gene ID: 7133), TNFRSF4 (OX40, CD134; NCBI Gene ID:7293), TNFRSF5 (CD40; NCBI Gene ID: 958), TNFRSF6 (FAS, NCBI Gene ID:355), TNFRSF7 (CD27, NCBI Gene ID: 939), TNFRSF8 (CD30, NCBI Gene ID:943), TNFRSF9 (4-1BB, CD137, NCBI Gene ID: 3604), TNFRSF10A (CD261, DR4,TRAILR1, NCBI Gene ID: 8797), TNFRSF10B (CD262, DR5, TRAILR², NCBI GeneID: 8795), TNFRSF10C (CD263, TRAILR3, NCBI Gene ID: 8794), TNFRSF10D(CD264, TRAILR4, NCBI Gene ID: 8793), TNFRSF11A (CD265, RANK, NCBI GeneID: 8792), TNFRSF11B (NCBI Gene ID: 4982), TNFRSF12A (CD266, NCBI GeneID: 51330), TNFRSF13B (CD267, NCBI Gene ID: 23495), TNFRSF13C (CD268,NCBI Gene ID: 115650), TNFRSF16 (NGFR, CD271, NCBI Gene ID: 4804),TNFRSF17 (BCMA, CD269, NCBI Gene ID: 608), TNFRSF18 (GITR, CD357, NCBIGene ID: 8784), TNFRSF19 (NCBI Gene ID: 55504), TNFRSF21 (CD358, DR6,NCBI Gene ID: 27242), and TNFRSF25 (DR3, NCBI Gene ID: 8718).

Examples anti-TNFRSF4 (OX40) antibodies that can be co-administeredinclude without limitation, MEDI6469, MEDI6383, MEDI0562(tavolixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998,INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and those described inWO2016179517, WO2017096179, WO2017096182, WO2017096281, andWO2018089628.

Examples anti-TNF receptor superfamily member 10b (TNFRSF10B, DR5,TRAILR2) antibodies that can be co-administered include withoutlimitation, such as DS-8273, CTB-006, INB RX-109, GEN-1029;

Examples of anti-TNFRSF5 (CD40) antibodies that can be co-administeredinclude without limitation RG7876, SEA-CD40, APX-005M and ABBV-428,ABBV-927, JNJ-64457107.

Examples of anti-TNFRSF7 (CD27) that can be co-administered includewithout limitation varlilumab (CDX-1127).

Example anti-TNFRSF9 (4-1BB, CD137) antibodies that can beco-administered include without limitation urelumab, utomilumab(PF-05082566), AGEN2373 and ADG-106.

Examples of anti-TNFRSF17 (BCMA) that can be co-administered includewithout limitation GSK-2857916.

Examples of anti-TNFRSF18 (GITR) antibodies that can be co-administeredinclude without limitation, MEDI1873, FPA-154, INCAGN-1876, TRX-518,BMS-986156, MK-1248, GWN-323, and those described in WO2017096179,WO2017096276, WO2017096189, and WO2018089628. In some embodiments, anantibody, or fragment thereof, co-targeting TNFRSF4 (OX40) and TNFRSF18(GITR) is co-administered. Such antibodies are described, e.g., inWO2017096179 and WO2018089628.

Example anti-TRAILR1, anti-TRAILR², anti-TRAILR3, anti-TRAILR4antibodies that can be co-administered include without limitationABBV-621.

Examples of Bi-specific antibodies targeting TNFRSF family members thatcan be co-administered include without limitation PRS-343 (CD-137/HER2),AFM26 (BCMA/CD16A), AFM-13 (CD16/CD30), REGN-1979 (CD20/CD3), AMG-420(BCMA/CD3), INHIBRX-105 (4-1BB/PDL1), FAP-4-IBBL (4-1BB/FAP), XmAb-13676(CD3/CD20), RG-7828 (CD20/CD3), CC-93269 (CD3/BCMA), REGN-5458(CD3/BCMA), and IMM-0306 (CD47/CD20), AMG-424 (CD38.CD3).

Adenosine Generation and Signaling

In various embodiments, a compound as described herein, is combined withan agonist or antagonist of AlR, A2AR, A2BR, A3R, CD73, CD39, CD26.

Examples of Adenosine A3 receptor (A3R) agonists include namodenoson(CF₁₀₂);

Examples of A2aR/A2bR antagonists include AB928;

Examples of anti-CD73 antibodies include MEDI-9447 (oleclumab), CPX-006,IPH-53, BMS-986179, NZV-930, CPI-006;

Examples of CD73 inhibitors include AB-680, PSB-12379, PSB-12441,PSB-12425, CB-708;

Examples of CD39/CD73 inhibitors include PBF-1662;

Examples of anti-CD39 antibodies include TTX-030;

Examples of Adenosine A2A receptor antagonists include CPI-444,AZD-4635, preladenant, PBF-509;

Examples of Adenosine deaminase inhibitors include pentostatin,cladribine;

Examples of Adenosine deaminase inhibitors include pentostatin,cladribine.

FLT3 Agonist

In various embodiments, a compound as described herein, is combined withan agonist of FLT3 (FLK2, STK1, CD135, FLK-2, Gene ID: 2322).

Examples of FLT3 agonist include without limitation, GS-3583, Sym-027,FLT3 agonist antibody (solid tumors), RIVAL-01, CDX-301, ONCR-177.

c-kit Targeting Agents

In various embodiments, a compound as described herein, is combined withan inhibitor of c-kit (PBT, SCFR, CD117, MASTC; NCBI Gene ID: 3815).

Examples of c-kit inhibitors include imatinib mesylate, JSP-191,BLU-263, CD117-ADC, AZD3229 (c-kit/PDGFR inhibitor), telatinib(c-kit/PDGF/VEGF2 inhibitor), quizartinib dihydrochloride (FLT3/c-kit),pexidartinib hydrochloride (CSF1R/FLT3/c-kit), avapritinib (PDGFR/c-Kitinhibitor), vorolanib (multikinase VEGF/PDGFR/c-kit inhibitor), andripretinib (c-kit/PDGFR^(a) inhibitor);

Examples of c-kit multi-kinase inhibitors include dasatinib, imatinib,nilotinib, sorafenib, lenvatinib mesylate, cabozantinib malate, AL-8326,ZLJ-33, KBP-7018, sunitinib malate, pazopanib derivatives, AGX-73,rebastinib, NMS-088, lucitanib hydrochloride, midostaurin, cediranib,dovitinib, sitravatinib, tivozanib, masitinib, regorafenib, HQP-1351,cabozantinib, ponatinib, and famitinib L-malate. Examples of anti-c-kitantibodies include CDX-0158, CDX-0159 and FSI-174.

SIRPalpha Targeting Agents

In various embodiments, a compound as described herein, is combined withan inhibitor of SIRPalpha (NCBI Gene ID: 140885).

Examples of SIRPalpha inhibitors include AL-008, RRx-001, and CTX-5861.

Examples of anti-SIRPalpha-antibodies include FSI-189, ES-004, BI765063,ADU1805, and CC-95251.

Bi-Specific T-Cell Engagers

In various embodiments, a compound as described herein, is combined witha bi-specific T-cell engager (e.g., not having an Fc) or an anti-CD3bi-specific antibody (e.g., having an Fc). Illustrative anti-CD3bi-specific antibodies or BiTEs that can be co-administered includeAMG-160 (PSMA/CD3), AMG-212 (PSMA/CD3), AMG-330 (CD33/CD3), AMG-420(BCMA/CD3), AMG-427 (FLT3/CD3), AMG-562 (CD19/CD3), AMG-596(EGFRvIII/CD3), AMG-673 (CD33/CD3), AMG-701 (BCMA/CD3), AMG-757(DLL3/CD3), JNJ-64052781 (CD19/CD3), AMG-211 (CEA/CD3), BLINCYTO®(CD19/CD3), RG7802 (CEA/CD3), ERY-974 (CD3/GPC3), huGD2-BsAb (CD3/GD2),PF-06671008 (Cadherins/CD3), APV0436 (CD123/CD3), ERY974, flotetuzumab(CD123/CD3), GEM333 (CD3/CD33), GEMoab (CD3/PSCA), REGN-1979 (CD20/CD3),REGN-5678 (PSMA/CD28), MCLA-117 (CD3/CLEC12A), JNJ-0819, JNJ-7564(CD3/heme), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33), MGD-009(CD3/B7H3), IMCgp100 (CD3/gp100), XmAb-14045 (CD123/CD3), XmAb-13676(CD3/CD20), XmAb-18087 (SSTR2/CD3), catumaxomab (CD3/EpCAM), REGN-4018(MUC16/CD3), RG6026, RG6076, RG6194, RG-7828 (CD20/CD3), CC-93269(CD3/BCMA), REGN-5458 (CD3/BCMA), GRB-1302 (CD3/Erbb2), GRB-1342(CD38/CD3), GEM-333 (CD3/CD33), PF-06863135 (BCMA/CD3), SAR440234(CD3/CDw123). As appropriate, the anti-CD3 binding bi-specific moleculesmay or may not have an Fc. Illustrative bi-specific T-cell engagers thatcan be co-administered target CD3 and a tumor-associated antigen asdescribed herein, including, e.g., CD19 (e.g., blinatumomab); CD33(e.g., AMG330); CEA (e.g., MEDI-565); receptor tyrosine kinase-likeorphan receptor 1 (ROR1) (Gohil, et al., Oncoimmunology. (2017) May 17;6(7):e1326437); PD-L1 (Horn, et al., Oncotarget. 2017 Aug. 3;8(35):57964-57980); and EGFRvIII (Yang, et al., Cancer Lett. 2017 Sep.10; 403:224-230).

Bi- and Tri-Specific Natural Killer (NK)-Cell Engagers

In various embodiments, a compound as described herein, is combined witha bi-specific NK-cell engager (BiKE) or a tri-specific NK-cell engager(TriKE) (e.g., not having an Fc) or bi-specific antibody (e.g., havingan Fc) against an NK cell activating receptor, e.g., CD16A, C-typelectin receptors (CD94/NKG2C, NKG2D, NKG2E/H and NKG2F), naturalcytotoxicity receptors (NKp30, NKp44 and NKp46), killer cell C-typelectin-like receptor (NKp65, NKp80), Fc receptor FcγR (which mediatesantibody-dependent cell cytotoxicity), SLAM family receptors (e.g., 2B4,SLAM6 and SLAM7), killer cell immunoglobulin-like receptors (KIR)(KIR-2DS and KIR-3DS), DNAM-1 and CD137 (41BB). Illustrative anti-CD16bi-specific antibodies, BiKEs or TriKEs that can be co-administeredinclude AFM26 (BCMA/CD16A) and AFM-13 (CD16/CD30). As appropriate, theanti-CD16 binding bi-specific molecules may or may not have an Fc.Illustrative bi-specific NK-cell engagers that can be co-administeredtarget CD16 and one or more tumor-associated antigens as describedherein, including, e.g., CD19, CD20, CD22, CD30, CD33, CD123, EGFR,EpCAM, ganglioside GD2, HER2/neu, HLA Class II and FOLR1. BiKEs andTriKEs are described, e.g., in Felices, et al., Methods Mol Biol. (2016)1441:333-346; Fang, et al., Semin Immunol. (2017) 31:37-54.

MCL1 Apoptosis Regulator, BCL2 Family Member (MCL1) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of MCL1 apoptosis regulator, BCL2 family member (MCL1, TM;EAT; MCL1L; MCL1S; Mc1-1; BCL2L3; MCL1-ES; bcl2-L-3; mcll/EAT; NCBI GeneID: 4170). Examples of MCL1 inhibitors include AMG-176, AMG-397,S-64315, and AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, and thosedescribed in WO2018183418, WO2016033486, and WO2017147410.

Hematopoietic Progenitor Kinase 1 (HPK1) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of mitogen-activated protein kinase kinase kinase kinase 1(MAP4K1, HPK1; NCBI Gene ID: 11184). Examples of HematopoieticProgenitor Kinase 1 (HPK1) inhibitors include without limitation, thosedescribed in WO-2018183956, WO-2018183964, WO-2018167147, WO-2018183964,WO-2016205942, WO-2018049214, WO-2018049200, WO-2018049191,WO-2018102366, WO-2018049152 and WO-2016090300.

Apoptosis Signal-Regulating Kinase (ASK) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of an ASK inhibitor, e.g., mitogen-activated protein kinasekinase kinase 5 (MAP3K5; ASK1, MAPKKKS, MEKKS; NCBI Gene ID: 4217).Examples of ASK1 inhibitors include without limitation, those describedin WO 2011/008709 (Gilead Sciences) and WO2013/112741 (Gilead Sciences).

Bruton Tyrosine Kinase (BTK) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of Bruton tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3,IMD1, PSCTK1, XLA; NCBI Gene ID: 695). Examples of BTK inhibitorsinclude without limitation,(S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one,acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib(Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059),PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531,SHR-1459, DTRMWXHS-12, TAS-5315, Calquence+AZD6738, andCalquence+danvatirsen.

Cyclin-Dependent Kinase (CDK) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of cyclin dependent kinase 1 (CDK1, CDC2; CDC28A; P34CDC2;NCBI Gene ID: 983); cyclin dependent kinase 2 (CDK2, CDKN2; p33 (CDK2);NCBI Gene ID: 1017); cyclin dependent kinase 3 (CDK3; NCBI Gene ID:1018); cyclin dependent kinase 4 (CDK4, CMM3; PSK-J3; NCBI Gene ID:1019); cyclin dependent kinase 6 (CDK6, MCPH12; PLSTIRE; NCBI Gene ID:1021); cyclin dependent kinase 7 (CDK7, CAK; CAK1; HCAK; M015; STK1;CDKN7; p39MO15; NCBI Gene ID: 1022); cyclin dependent kinase 9 (CDK9,TAK; C-2k; CTK1; CDC2L4; PITALRE; NCBI Gene ID: 1025). Inhibitors of CDK1, 2, 3, 4, 6, 7 and/or 9, include without limitation abemaciclib,alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, ibrance,FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01,SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib, PF-06873600,AZD4573, and TG-02.

Discoidin Domain Receptor (DDR) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of discoidin domain receptor tyrosine kinase 1 (DDR1, CAK,CD167, DDR, EDDR1, HGK2, MCK10, NEP, NTRK4, PTK3, PTK3A, RTK6, TRKE;NCBI Gene ID: 780); and/or discoidin domain receptor tyrosine kinase 2(DDR², MIG20a, NTRKR3, TKT, TYR010, WRCN; NCBI Gene ID: 4921). Examplesof DDR inhibitors include without limitation, dasatinib and thosedisclosed in WO2014/047624 (Gilead Sciences), US 2009-0142345 (TakedaPharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO2013/027802 (Chugai Pharmaceutical), and WO2013/034933 (ImperialInnovations).

Histone Deacetylase (HDAC) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of a histone deacetylase, e.g., histone deacetylase 9(HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP,MITR; Gene ID: 9734). Examples of HDAC inhibitors include withoutlimitation, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581,CS-055 (HBI-8000), CUDC-907 (fimepinostat), entinostat, givinostat,mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585),resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat,tinostamustine, remetinostat, entinostat, romidepsin, tucidinostat.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID:3620). Examples of IDO1 inhibitors include without limitation, BLV-0801,epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod,NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinonederivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, andshIDO-ST, EOS-200271, KHK-2455, LY-3381916.

Janus Kinase (JAK) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of Janus kinase 1 (JAK1, JAK1A, JAK1B, JTK3; NCBI Gene ID:3716); Janus kinase 2 (JAK2, JTK10, THCYT3; NCBI Gene ID: 3717); and/orJanus kinase 3 (JAK3, JAK-3, JAK3 HUMAN, JAKL, L-JAK, LJAK; NCBI GeneID: 3718). Examples of JAK inhibitors include without limitation,AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib(GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib),lestaurtinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518),peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib),INCB052793, and XL019.

Matrix Metalloprotease (MMP) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of a matrix metallopeptidase (MMP), e.g., an inhibitor ofMMP1 (NCBI Gene ID: 4312), MMP2 (NCBI Gene ID: 4313), MMP3 (NCBI GeneID: 4314), MMP1 (NCBI Gene ID: 4316), MMP8 (NCBI Gene ID: 4317), MMP9(NCBI Gene ID: 4318); MMP10 (NCBI Gene ID: 4319); MMP11 (NCBI Gene ID:4320); MMP12 (NCBI Gene ID: 4321), MMP13 (NCBI Gene ID: 4322), MMP14(NCBI Gene ID: 4323), MMP15 (NCBI Gene ID: 4324), MMP16 (NCBI Gene ID:4325), MMP17 (NCBI Gene ID: 4326), MMP19 (NCBI Gene ID: 4327), MMP20(NCBI Gene ID: 9313), MMP21 (NCBI Gene ID: 118856), MMP24 (NCBI Gene ID:10893), MMP25 (NCBI Gene ID: 64386), MMP26 (NCBI Gene ID: 56547), MMP27(NCBI Gene ID: 64066) and/or MMP28 (NCBI Gene ID: 79148). Examples ofMMP9 inhibitors include without limitation, marimastat (BB-2516),cipemastat (Ro 32-3555), GS-5745 (andecaliximab) and those described inWO 2012/027721 (Gilead Biologics).

RAS and RAS Pathway Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of KRAS proto-oncogene, GTPase (KRAS; a.k.a., NS; NS3;CFC2; RALD; K-Ras; KRAS1; KRAS2; RASK2; KI-RAS; C—K-RAS; K-RAS2A;K-RAS2B; K-RAS4A; K-RAS4B; c-Ki-ras2; NCBI Gene ID: 3845); NRASproto-oncogene, GTPase (NRAS; a.k.a., NS6; CMNS; NCMS; ALPS4; N-ras;NRAS1; NCBI Gene ID: 4893); HRas proto-oncogene, GTPase (HRAS; a.k.a.,CTLO; KRAS; HAMSV; HRAS1; KRAS2; RASH1; RASK2; Ki-Ras; p2lras; C—H-RAS;c-K-ras; H-RASIDX; c-Ki-ras; C-BAS/HAS; C-HA-RAS1; NCBI Gene ID: 3265);. The Ras inhibitors can inhibit Ras at either the polynucleotide (e.g.,transcriptional inhibitor) or polypeptide (e.g., GTPase enzymeinhibitor) level. In some embodiments, the inhibitors target one or moreproteins in the Ras pathway, e.g., inhibit one or more of EGFR, Ras, Raf(A-Raf, B-Raf, C-Raf), MEK (MEK1, MEK2), ERK, PI3K, AKT and mTOR.

In various embodiments, a compound as described herein, is combined withan inhibitor of KRAS. Examples of KRAS inhibitors include AMG-510,COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406, BI-1701963,ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D), Kobe0065/2602(Ras GTP), RT11, MRTX-849 (G12C) and K-Ras (G12D)-selective inhibitorypeptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH₂) (SEQ ID NO:108) andKRpep-2d (Ac-RRRRCPLYISYDPVCRRRR-NH₂) (SEQ ID NO:109).

In various embodiments, a compound as described herein, is combined withan inhibitor of KRAS mRNA. Illustrative KRAS mRNA inhibitors includeanti-KRAS Ul adaptor, AZD-4785, siG12D-LODER™, and siG12D exosomes.

In various embodiments, a compound as described herein, is combined withan inhibitor of MEK. Illustrative MEK inhibitors that can beco-administered include binimetinib, cobimetinib, PD-0325901,pimasertib, RG-7304, selumetinib, and trametinib.

In various embodiments, a compound as described herein, is combined withan inhibitor of AKT. Illustrative AKT inhibitors that can beco-administered include RG7440, MK-2206, ipatasertib, afuresertib,AZD5363, and ARQ-092, capivasertib, triciribine, ABTL-0812(PI3K/Akt/mTOR).

In various embodiments, a compound as described herein, is combined withan inhibitor of Raf. Illustrative Raf inhibitors that can beco-administered BGB-283 (Raf/EGFR), HM-95573, LXH-254, LY-3009120,RG7304, TAK-580, dabrafenib, vemurafenib, encorafenib (LGX818), PLX8394.RAF-265 (Raf/VEGFR), ASN-003 (Raf/PI3K).

In various embodiments, a compound as described herein, is combined withan inhibitor of ERK. Illustrative ERK inhibitors that can beco-administered include LTT-462, LY-3214996, MK-8353, ravoxertinib,GDC-0994, and ulixertinib.

In various embodiments, a compound as described herein, is combined withan inhibitor of PI3K. Illustrative PI3K inhibitors that can beco-administered include idelalisib (Zydelig®), alpelisib, buparlisib,and pictilisib. Illustrative PI3K/mTOR inhibitors that can beco-administered include dactolisib, omipalisib, voxtalisib, gedatolisib,GSK2141795, and RG6114.

In various embodiments, a compound as described herein, is combined withan inhibitor of mTOR. Illustrative mTOR inhibitors that can beco-administered include as sapanisertib, vistusertib (AZD2014), ME-344,sirolimus (oral nano-amorphous formulation, cancer), and TYME-88(mTOR/cytochrome P450 3A4).

In certain embodiments, Ras-driven cancers (e.g., NSCLC) having CDKN2Amutations can be inhibited by co-administration of the MEK inhibitorselumetinib and the CDK4/6 inhibitor palbociclib. See, e.g., Zhou, etal., Cancer Lett. 2017 Nov. 1; 408:130-137. Also, K-RAS and mutant N-RAScan be reduced by the irreversible ERBB1/2/4 inhibitor neratinib. See,e.g., Booth, et al., Cancer Biol Ther. 2018 Feb. 1; 19(2):132-137.

In various embodiments, a compound as described herein, is combined withan inhibitor of RAS. Examples of RAS inhibitors include NEO-100, andrigosertib.

In various embodiments, a compound as described herein, is combined withan antagonist of EGFR, such as AMG-595, necitumumab, ABBV-221,depatuxizumab mafodotin (ABT-414), tomuzotuximab, ABT-806, vectibix,modotuximab, or RM-1929.

In various embodiments, a compound as described herein, is combined withan inhibitor of protein tyrosine phosphatase non-receptor type 11(PTPN11; BPTP3, CFC, JMML, METCDS, NS1, PTP-1D, PTP2C, SH-PTP2, SH-PTP3,SHP2; NCBI Gene ID: 5781).

Examples of SHP2 inhibitors include TN0155 (SHP-099), RMC-4550,JAB-3068, RMC-4630, SAR442720 and those described in WO2018172984 andWO2017211303.

In various embodiments, a compound as described herein, is combined withan inhibitor of mitogen-activated protein kinase 7 (MAP2K7, JNKK2,MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID: 5609).Examples of MEK inhibitors include antroquinonol, binimetinib, CK-127,cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244),sorafenib, trametinib (GSK1120212), uprosertib+trametinib, PD-0325901,pimasertib, LTT462, AS703988, CC-90003, refametinib, TAK-733, CI-1040,RG7421.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of a phosphatidylinositol-4,5-bisphosphate 3-kinasecatalytic subunit, e.g., phosphatidylinositol-4,5-bisphosphate 3-kinasecatalytic subunit alpha (PIK3CA, CLAPO, CLOVE, CWSS, MCAP, MCM, MCMTC,PI3K, PI3K-alpha, p110-alpha; NCBI Gene ID: 5290);phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta(PIK3CB, P110BETA, PI3K, PI3KBETA, PIK3C1; NCBI Gene ID: 5291);phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma(PIK3CG, PI3CG, PI3K, PI3Kgamma, PIK3, p110gamma, p120-PI3K; Gene ID:5494); and/or phosphatidylinositol-4,5-bisphosphate 3-kinase catalyticsubunit delta (PIK3CD, APDS, IMD14, P110DELTA, PI3K, p110D, NCBI GeneID: 5293). In some embodiments, the PI3K inhibitor is a pan-PI3Kinhibitor. Examples of PI3K inhibitors include without limitation,ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235,buparlisib (BKM120), BYL719 (alpelisib), CH₅₁₃₂₇₉₉, copanlisib (BAY80-6946), duvelisib, GDC-0032, GDC-0077, GDC-0941, GDC-0980, GSK2636771,GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI-549,KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604,rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202(umbralisib), TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499,XL756, wortmannin, ZSTK474, and the compounds described in WO2005/113556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO 2013/116562(Gilead Calistoga), WO 2014/100765 (Gilead Calistoga), WO 2014/100767(Gilead Calistoga), and WO 2014/201409 (Gilead Sciences).

Mitogen-Activated Protein Kinase (MEK) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of mitogen-activated protein kinase kinase 7 (MAP2K7,JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7, SAPKK-4, SAPKK4; NCBI Gene ID:5609). Examples of MEK inhibitors include antroquinonol, binimetinib,cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244),sorafenib, trametinib (GSK1120212), uprosertib+trametinib, PD-0325901,pimasertib, LTT462, AS703988, CC-90003, refametinib.

Spleen Tyrosine Kinase (SYK) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of spleen associated tyrosine kinase (SYK, p72-Syk, GeneID: 6850). Examples of SYK inhibitors include without limitation,6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine,BAY-61-3606, cerdulatinib (PRT-062607), entospletinib, fostamatinib(R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), andthose described in U.S. Pat. No. 8,450,321 (Gilead Connecticut) andthose described in U.S. 2015/0175616.

Toll-Like Receptor (TLR) Agonists

In various embodiments, a compound as described herein, is combined withan agonist of a toll-like receptor (TLR), e.g., an agonist of TLR1 (NCBIGene ID: 7096), TLR2 (NCBI Gene ID: 7097), TLR3 (NCBI Gene ID: 7098),TLR4 (NCBI Gene ID: 7099), TLR5 (NCBI Gene ID: 7100), TLR6 (NCBI GeneID: 10333), TLR7 (NCBI Gene ID: 51284), TLR8 (NCBI Gene ID: 51311), TLR9(NCBI Gene ID: 54106), and/or TLR10 (NCBI Gene ID: 81793). Example TLR7agonists that can be co-administered include without limitation DS-0509,GS-9620, LHC-165, TMX-101 (imiquimod), GSK-2245035, resiquimod,DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922,3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7795, and the compoundsdisclosed in US20100143301 (Gilead Sciences), US20110098248 (GileadSciences), and US20090047249 (Gilead Sciences), US20140045849 (Janssen),US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221(Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen),WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050(Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485(Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (VentirxPharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma),US20140088085 (Ventirx Pharma), US20140275167 (Novira Therapeutics), andUS20130251673 (Novira Therapeutics). An TLR7/TLR8 agonist that can beco-administered is NKTR-262. Example TLR8 agonists that can beco-administered include without limitation E-6887, IMO-4200, IMO-8400,IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, GS-9688, VTX-1463,VTX-763, 3M-051, 3M-052, and the compounds disclosed in US20140045849(Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen),WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031(Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma),US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma),US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma),US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma),US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma),US20140275167 (Novira Therapeutics), and US20130251673 (NoviraTherapeutics). Example TLR9 agonists that can be co-administered includewithout limitation AST-008, CMP-001, IMO-2055, IMO-2125, litenimod,MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200,agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, leftolimod(MGN-1703), CYT-003, CYT-003-QbG10 and PUL-042. Examples of TLR3 agonistinclude rintatolimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33,MCT-465, MCT-475, and ND-1.1.

Examples of TLR8 inhibitors include, but are not limited to, E-6887,IMO-8400, IMO-9200 and VTX-763.

Examples of TLR8 agonists include, but are not limited to, MCT-465,motolimod, GS-9688, and VTX-1463.

Examples of TLR9 inhibitors include but are not limited to, AST-008,IMO-2055, IMO-2125, lefitolimod, litenimod, MGN-1601, and PUL-042.

Examples of TLR7/TLR8 agonist, such as NKTR-262, IMO-4200, MEDI-9197(telratolimod), resiquimod;

Examples of TLR agonists include without limitation: lefitolimod,tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod,AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688,LHC-165, BDB-001, RG-7854, telratolimod.

Stimulator of Interferon Genes (STING)

some embodiments, the therapeutic agent is a stimulator of interferongenes (STING) In some embodiments, the STING receptor agonist oractivator is selected from the group consisting of ADU-S100 (MIW-815),SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1,SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic-GAMP(cGAMP) and cyclic-di-AMP.

Tyrosine-Kinase Inhibitors (TKIs)

In various embodiments, a compound as described herein, is combined witha tyrosine kinase inhibitor (TKI). TKIs may target epidermal growthfactor receptors (EGFRs) and receptors for fibroblast growth factor(FGF), platelet-derived growth factor (PDGF), and vascular endothelialgrowth factor (VEGF). Examples of TKIs include without limitation,axitinib, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547,bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib,dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, gefitinib,gilteritinib (ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391(Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib,ODM-203, olmutinib, osimertinib (AZD-9291), pazopanib, ponatinib,poziotinib, quizartinib, radotinib, rociletinib, sulfatinib (HMPL-012),sunitinib, famitinib L-malate, (MAC-4), tivoanib, TH-4000, tivoanib, andMEDI-575 (anti-PDGFR antibody), TAK-659, Cabozantinib.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) Inhibitors

In various embodiments, a compound as described herein, is combined withan inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI Gene ID:3620). Examples of IDO1 inhibitors include without limitation, BLV-0801,epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod,NKTR-218, NLG-919-based vaccine, PF-06840003, pyranonaphthoquinonederivatives (SN-35837), resminostat, SBLK-200802, BMS-986205, andshIDO-ST, EOS-200271, KHK-2455, LY-3381916.

Chemotherapeutic Agents

In various embodiments, a compound as described herein, is combined witha chemotherapeutic agent or anti-neoplastic agent.

As used herein, the term “chemotherapeutic agent” or “chemotherapeutic”(or “chemotherapy” in the case of treatment with a chemotherapeuticagent) is meant to encompass any non-proteinaceous (e.g., non-peptidic)chemical compound useful in the treatment of cancer. Examples ofchemotherapeutic agents include but not limited to: alkylating agentssuch as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates suchas busulfan, improsulfan, and piposulfan; aziridines such as benzodepa,carboquone, meturedepa, and uredepa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide, and trimemylolomelamine; acetogenins,e.g., bullatacin and bullatacinone; a camptothecin, including syntheticanalog topotecan; bryostatin, callystatin; CC-1065, including itsadozelesin, carzelesin, and bizelesin synthetic analogs; cryptophycins,particularly cryptophycin 1 and cryptophycin 8; dolastatin; duocarmycin,including the synthetic analogs KW-2189 and CBI-TMI; eleutherobin;5-azacytidine; pancratistatin; a sarcodictyin; spongistatin; nitrogenmustards such as chlorambucil, chlornaphazine, cyclophosphamide,glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, and uracilmustard; nitrosoureas such as carmustine, chlorozotocin, foremustine,lomustine, nimustine, and ranimustine; antibiotics such as the enediyneantibiotics (e.g., calicheamicin, especially calicheamicin gammall andcalicheamicin phill), dynemicin including dynemicin A, bisphosphonatessuch as clodronate, an esperamicin, neocarzinostatin chromophore andrelated chromoprotein enediyne antibiotic chromomophores,aclacinomycins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, carabicin, carrninomycin, carzinophilin, chromomycins,dactinomycin, daunorubicin, detorubicin, 6-diazo-doxorubicin (includingmorpholino-doxorubicin, cyanomorpholino-doxorubicin,2-pyrrolino-doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolicacid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, and zorubicin; anti-metabolites such asmethotrexate and 5-fluorouracil (5-FU); folic acid analogs such asdemopterin, methotrexate, pteropterin, and trimetrexate; purine analogssuch as cladribine, pentostatin, fludarabine, 6-mercaptopurine,thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine,azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine,doxifluridine, enocitabine, and floxuridine; androgens such ascalusterone, dromostanolone propionate, epitiostanol, mepitiostane, andtestolactone; anti-adrenals such as aminoglutethimide, mitotane, andtrilostane; folic acid replinishers such as frolinic acid;radiotherapeutic agents such as Radium-223, 177-Lu-PSMA-617;trichothecenes, especially T-2 toxin, verracurin A, roridin A, andanguidine; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel(TAXOTERE®), cabazitaxel, BIND-014, tesetaxel; platinum analogs such ascisplatin and carboplatin, NC-6004 nanoplatin; aceglatone;aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine;hestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformthine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine;maytansinoids such as maytansine and ansamitocins; mitoguazone;mitoxantrone; mopidamol; nitracrine; phenamet; pirarubicin;losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid;2-ethylhydrazide; procarbazine; poly saccharide-K (PSK); razoxane;rhizoxin; sizofiran; spirogermanium; tenuazonic acid; trabectedin,triaziquone; 2,2′,2″-trichlorotriemylamine; urethane; vindesine;dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiopeta;chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine;methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitroxantrone; vancristine; vinorelbine (NAVELBINE®); novantrone;teniposide; edatrexate; daunomycin; aminopterin; xeoloda; ibandronate;CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine(DFMO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFOX(folinic acid, 5-fluorouracil, oxaliplatin); FOLFIRI (folinic acid,5-fluorouracil, irinotecan); FOLFOXIRI (folinic acid, 5-fluorouracil,oxaliplatin, irinotecan), FOLFIRINOX (folinic acid, 5-fluorouracil,irinotecan, oxaliplatin), and pharmaceutically acceptable salts, acids,or derivatives of any of the above. Such agents can be conjugated ontoan antibody or any targeting agent described herein to create anantibody-drug conjugate (ADC) or targeted drug conjugate.

Anti-Hormonal Agents

Also included in the definition of “chemotherapeutic agent” areanti-hormonal agents such as anti-estrogens and selective estrogenreceptor modulators (SERMs), inhibitors of the enzyme aromatase,anti-androgens, and pharmaceutically acceptable salts, acids orderivatives of any of the above that act to regulate or inhibit hormoneaction on tumors.

Examples of anti-estrogens and SERMs include, for example, tamoxifen(including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY117018, onapristone, and toremifene(FARESTON®).

Inhibitors of the enzyme aromatase regulate estrogen production in theadrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide,megestrol acetate (MEGACE®), exemestane, formestane, fadrozole, vorozole(RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®).

Examples of anti-androgens include apalutamide, abiraterone,enzalutamide, flutamide, galeterone, nilutamide, bicalutamide,leuprolide, goserelin, ODM-201, APC-100, ODM-204.

An example progesterone receptor antagonist includes onapristone.

Anti-Angiogenic Agents

In various embodiments, a compound as described herein, is combined withan anti-angiogenic agent. Anti-angiogenic agents that can beco-administered include, but are not limited to, retinoid acid andderivatives thereof, 2-methoxyestradiol, ANGIOSTATIN®, ENDOSTATIN®,regorafenib, necuparanib, suramin, squalamine, tissue inhibitor ofmetalloproteinase-1, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inbibitor-2,cartilage-derived inhibitor, paclitaxel (nab-paclitaxel), plateletfactor 4, protamine sulphate (clupeine), sulphated chitin derivatives(prepared from queen crab shells), sulphated polysaccharidepeptidoglycan complex (sp-pg), staurosporine, modulators of matrixmetabolism including proline analogs such as 1-azetidine-2-carboxylicacid (LACA), cishydroxyproline, d,I-3,4-dehydroproline, thiaproline,α,α′-dipyridyl, beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chicken inhibitor ofmetalloproteinase-3 (ChIMP-3), chymostatin, beta-cyclodextrintetradecasulfate, eponemycin, fumagillin, gold sodium thiomalate,d-penicillamine, beta-1-anticollagenase-serum, alpha-2-antiplasmin,bisantrene, lobenzarit disodium, n-2-carboxyphenyl-4-chloroanthronilicacid disodium or “CCA”, thalidomide, angiostatic steroid, carboxyaminoimidazole, metalloproteinase inhibitors such as BB-94, inhibitorsof S100A9 such as tasquinimod. Other anti-angiogenesis agents includeantibodies, preferably monoclonal antibodies against these angiogenicgrowth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C,HGF/SF, and Ang-1/Ang-2.

Anti-Fibrotic Agents

In various embodiments, a compound as described herein, is combined withan anti-fibrotic agent. Anti-fibrotic agents that can be co-administeredinclude, but are not limited to, the compounds such asbeta-aminoproprionitrile (BAPN), as well as the compounds disclosed inU.S. Pat. No. 4,965,288 relating to inhibitors of lysyl oxidase andtheir use in the treatment of diseases and conditions associated withthe abnormal deposition of collagen and U.S. Pat. No. 4,997,854 relatingto compounds which inhibit LOX for the treatment of various pathologicalfibrotic states, which are herein incorporated by reference. Furtherexemplary inhibitors are described in U.S. Pat. No. 4,943,593 relatingto compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine,U.S. Pat. Nos. 5,021,456, 5,059,714, 5,120,764, 5,182,297, 5,252,608relating to 2-(1-naphthyloxymemyl)-3-fluoroallylamine, and US2004-0248871, which are herein incorporated by reference.

Exemplary anti-fibrotic agents also include the primary amines reactingwith the carbonyl group of the active site of the lysyl oxidases, andmore particularly those which produce, after binding with the carbonyl,a product stabilized by resonance, such as the following primary amines:emylenemamine, hydrazine, phenylhydrazine, and their derivatives;semicarbazide and urea derivatives; aminonitriles such as BAPN or2-nitroethylamine; unsaturated or saturated haloamines such as2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine,3-bromopropylamine, and p-halobenzylamines; and selenohomocysteinelactone.

Other anti-fibrotic agents are copper chelating agents penetrating ornot penetrating the cells. Exemplary compounds include indirectinhibitors which block the aldehyde derivatives originating from theoxidative deamination of the lysyl and hydroxylysyl residues by thelysyl oxidases. Examples include the thiolamines, particularlyD-penicillamine, and its analogs such as2-amino-5-mercapto-5-methylhexanoic acid,D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid,p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid,sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate,2-acetamidoethyl-2-acetamidoethanethiol sulphanate, andsodium-4-mercaptobutanesulphinate trihydrate.

Anti-Inflammatory Agents

In various embodiments, a compound as described herein, is combined withan anti-inflammatory agent. Example anti-inflammatory agents includewithout limitation inhibitors of one or more of arginase (ARG1 (NCBIGene ID: 383), ARG2 (NCBI Gene ID: 384)), carbonic anhydrase (CA1 (NCBIGene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761), CA4(NCBI Gene ID: 762), CASA (NCBI Gene ID: 763), CA5B (NCBI Gene ID:11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI GeneID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11(NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID:377677), CA14 (NCBI Gene ID: 23632)), prostaglandin-endoperoxidesynthase 1 (PTGS1, COX-1; NCBI Gene ID: 5742),prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2; NCBI Gene ID:5743), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES;Gene ID: 9536), arachidonate 5-lipoxygenase (ALOXS, 5-LOX; NCBI Gene ID:240), soluble epoxide hydrolase 2 (EPHX2, SEH; NCBI Gene ID: 2053)and/or mitogen-activated protein kinase kinase kinase 8 (MAP3K8, TPL2;NCBI Gene ID: 1326). In some embodiments, the inhibitor is a dualinhibitor, e.g., a dual inhibitor of COX-2/COX-1, COX-2/SEH, COX-2/CA,COX-2/5-LOX.

Examples of inhibitors of prostaglandin-endoperoxide synthase 1 (PTGS1,COX-1; NCBI Gene ID: 5742) that can be co-administered include withoutlimitation mofezolac, GLY-230, and TRK-700.

Examples of inhibitors of prostaglandin-endoperoxide synthase 2 (PTGS2,COX-2; NCBI Gene ID: 5743) that can be co-administered include withoutlimitation diclofenac, meloxicam, parecoxib, etoricoxib, AP-101,celecoxib, AXS-06, diclofenac potassium, DRGT-46, AAT-076, meisuoshuli,lumiracoxib, meloxicam, valdecoxib, zaltoprofen, nimesulide,Anitrazafen, Apricoxib, Cimicoxib, Deracoxib, Flumizole, Firocoxib,Mavacoxib, NS-398, Pamicogrel, Parecoxib, Robenacoxib, Rofecoxib,Rutecarpine, Tilmacoxib, and Zaltoprofen. Examples of dual COX1/COX2inhibitors that can be co-administered include without limitation,HP-5000, lornoxicam, ketorolac tromethamine, bromfenac sodium, ATB-346,HP-5000. Examples of dual COX-2/carbonic anhydrase (CA) inhibitors thatcan be co-administered include without limitation polmacoxib andimrecoxib.

Examples of inhibitors of secreted phospholipase A2, prostaglandin Esynthase (PTGES, PGES; Gene ID: 9536) that can be co-administeredinclude without limitation LY3023703, GRC 27864, and compounds describedin WO2015158204, WO2013024898, WO2006063466, WO2007059610, WO2007124589,WO2010100249, WO2010034796, WO2010034797, WO2012022793, WO2012076673,WO2012076672, WO2010034798, WO2010034799, WO2012022792, WO2009103778,WO2011048004, WO2012087771, WO2012161965, WO2013118071, WO2013072825,WO2014167444, WO2009138376, WO2011023812, WO2012110860, WO2013153535,WO2009130242, WO2009146696, WO2013186692, WO2015059618, WO2016069376,WO2016069374, WO2009117985, WO2009064250, WO2009064251, WO2009082347,WO2009117987, and WO2008071173. Metformin has further been found torepress the COX2/PGE2/STAT3 axis, and can be co-administered. See, e.g.,Tong, et al., Cancer Lett. (2017) 389:23-32; and Liu, et al.,Oncotarget. (2016) 7(19):28235-46.

Examples of inhibitors of carbonic anhydrase (e.g., one or more of CA1(NCBI Gene ID: 759), CA2 (NCBI Gene ID: 760), CA3 (NCBI Gene ID: 761),CA4 (NCBI Gene ID: 762), CASA (NCBI Gene ID: 763), CA5B (NCBI Gene ID:11238), CA6 (NCBI Gene ID: 765), CA7 (NCBI Gene ID: 766), CA8 (NCBI GeneID: 767), CA9 (NCBI Gene ID: 768), CA10 (NCBI Gene ID: 56934), CA11(NCBI Gene ID: 770), CA12 (NCBI Gene ID: 771), CA13 (NCBI Gene ID:377677), CA14 (NCBI Gene ID: 23632)) that can be co-administered includewithout limitation acetazolamide, methazolamide, dorzolamide,zonisamide, brinzolamide and dichlorphenamide. A dual COX-2/CA1/CA2inhibitor that can be co-administered includes CG100649.

Examples of inhibitors of arachidonate 5-lipoxygenase (ALOXS, 5-LOX;NCBI Gene ID: 240) that can be co-administered include withoutlimitation meclofenamate sodium, zileuton.

Examples of inhibitors of soluble epoxide hydrolase 2 (EPHX2, SEH; NCBIGene ID: 2053) that can be co-administered include without limitationcompounds described in WO2015148954. Dual inhibitors of COX-2/SEH thatcan be co-administered include compounds described in WO2012082647. Dualinhibitors of SEH and fatty acid amide hydrolase (FAAH; NCBI Gene ID:2166) that can be co-administered include compounds described inWO2017160861.

Examples of inhibitors of mitogen-activated protein kinase kinase kinase8 (MAP3K8, tumor progression loci-2, TPL2; NCBI Gene ID: 1326) that canbe co-administered include without limitation GS-4875, GS-5290, BHM-078and those described, e.g., in WO2006124944, WO2006124692, WO2014064215,WO2018005435, Teli, et al., J Enzyme Inhib Med Chem. (2012)27(4):558-70; Gangwall, et al., Curr Top Med Chem. (2013) 13(9):1015-35;Wu, et al., Bioorg Med Chem Lett. (2009) 19(13):3485-8; Kaila, et al.,Bioorg Med Chem. (2007) and Hu, et al., Bioorg Med Chem Lett. (2011)21(16):4758-61.

Tumor Oxygenation Agents

In various embodiments, a compound as described herein, is combined withan agent that promotes or increases tumor oxygenation or reoxygenation,or prevents or reduces tumor hypoxia. Illustrative agents that can beco-administered include, e.g., Hypoxia inducible factor-1 alpha (HIF-1α)inhibitors, such as PT-2977, PT-2385; VEGF inhibitors, such asbevasizumab, IMC-3C5, GNR-011, tanibirumab, LYN-00101, ABT-165; and/oran oxygen carrier protein (e.g., a heme nitric oxide and/or oxygenbinding protein (HNOX)), such as OMX-302 and HNOX proteins described inWO 2007/137767, WO 2007/139791, WO 2014/107171, and WO 2016/149562.

Immunotherapeutic Agents

In various embodiments, a compound as described herein, is combined withan immunotherapeutic agent. Example immunotherapeutic agents that can beco-administered include without limitation abagovomab, ABP-980,adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab,anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab,bevacizumab biosimilar, bivatuzumab, blinatumomab, brentuximab,cantuzumab, catumaxomab, CC49, cetuximab, citatuzumab, cixutumumab,clivatuzumab, conatumumab, dacetuzumab, dalotuzumab, daratumumab,detumomab, dinutuximab, drozitumab, duligotumab, dusigitumab,ecromeximab, elotuzumab, emibetuzumab, ensituximab, ertumaxomab,etaracizumab, farletuzumab, ficlatuzumab, figitumumab, flanvotumab,futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab,ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab,intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016, and MDX-101),iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab,lucatumumab, mapatumumab, matuzumab, milatuzumab, minretumomab,mitumomab, mogamulizumab, moxetumomab, moxetumomab pasudotox,naptumomab, narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833,obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab,oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox,patritumab, pemtumomab, pertuzumab, pintumomab, pritumumab, racotumomab,radretumab, ramucirumab (Cyramza®), rilotumumab, rituximab, robatumumab,samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab,tacatuzumab, taplitumomab, tenatumomab, teprotumumab, tigatuzumab,tositumomab, trastuzumab, trastuzumab biosimilar, tucotuzumab,ubilituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, and 3F8.Rituximab can be used for treating indolent B-cell cancers, includingmarginal-zone lymphoma, WM, CLL and small lymphocytic lymphoma. Acombination of Rituximab and chemotherapy agents is especiallyeffective.

The exemplified therapeutic antibodies may be further labeled orcombined with a radioisotope particle such as indium-111, yttrium-90(90Y-clivatuzumab), or iodine-131.

In some embodiments, the immunotherapeutic agent is an antibody-drugconjugate (ADC). Illustrative ADCs that can be co-administered includewithout limitation drug-conjugated antibodies, fragments thereof, orantibody mimetics targeting the proteins or antigens listed above andherein (e.g., in Table B). Example ADCs that can be co-administeredinclude without limitation gemtuzumab, brentuximab, trastuzumab,inotuzumab, glembatumumab, anetumab, mirvetuximab, depatuxizumab,rovalpituzumab, vadastuximab, labetuzumab, sacituzumab, lifastuzumab,indusatumab, polatzumab, pinatuzumab, coltuximab, indatuximab,milatuzumab, rovalpituzumab, ABB V-011, ABBV-2029, ABB V-321, ABB V-647,MLN0264 (anti-GCC, guanylyl cyclase C), T-DM1 (trastuzumab emtansine,Kadcycla); SYD985 (anti-HER², Duocarmycin), milatuzumab-doxorubicin(hCD74-DOX), brentuximab vedotin (ADCETRISC), DCDT2980S, belantamabmafodotin (GSK2857916), polatuzumab vedotin (RG-7596), SGN-CD70A,SGN-CD19A, inotuzumab ozogamicin (CMC-544), lorvotuzumab mertansine,SAR3419, isactuzumab govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME,DS-8201 ((trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402,177Lu-tetraxetan-tetuloma, tisotumab vedotin, anetumab ravtansine,CX-2009, SAR-566658, W-0101, ABBV-085, gemtuzumab ozogamicin, ABT-414,glembatumumab vedotin (CDX-011), labetuzumab govitecan (IMMU-130),sacituzumab govitecan (IMMU-132), lifastuzumab vedotin, (RG-7599),milatuzumab-doxorubicin (IMMU-110), indatuximab ravtansine (BT-062),pinatuzumab vedotin (RG-7593), SGN-LIV1A, SGN-CD33A, SAR566658, MLN2704,SAR408701, rovalpituzumab tesirine, ABBV-399, AGS-16C3F, ASG-22ME,AGS67E, AMG 172, AMG 595, AGS-15E, BAY1129980, BAY1187982, BAY94-934(anetumab ravtansine), GSK2857916, Humax-TF-ADC (tisotumab vedotin),IMGN289, IMGN529; IMGN853 (mirvetuximab soravtansine), LOP628, PCA062,MDX-1203, MEDI-547, PF-06263507, PF-06647020, PF-06647263, PF-06664178,PF-06688992, PF-06804103, RG7450, RG7458, RG7598, SAR566658, SGN-CD33A,DS-1602 and DS-7300, DS-6157, DS-6000, TAK-164, MEDI2228, MEDI7247,AMG575, . ADCs that can be co-administered are described, e.g., inLambert, et al., Adv Ther (2017) 34:1015-1035 and in de Goeij, CurrentOpinion in Immunology (2016) 40:14-23.

Illustrative therapeutic agents (e.g., anticancer or antineoplasticagents) that can be conjugated to the drug-conjugated antibodies,fragments thereof, or antibody mimetics include without limitationmonomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), acalicheamicin, ansamitocin, maytansine or an analog thereof (e.g.,mertansine/emtansine (DM1), ravtansine/soravtansine (DM4)), ananthracyline (e.g., doxorubicin, daunorubicin, epirubicin, idarubicin),pyrrolobenzodiazepine (PBD) DNA cross-linking agent SC-DR002 (D6.5),duocarmycin, a microtubule inhibitors (MTI) (e.g., a taxane, a vincaalkaloid, an epothilone), a pyrrolobenzodiazepine (PBD) or dimerthereof, a duocarmycin (A, B1, B2, C1, C2, D, SA, CC-1065), and otheranticancer or anti-neoplastic agents described herein.

Cancer Gene Therapy and Cell Therapy

In various embodiments, a compound as described herein, is combined witha cancer gene therapy and cell therapy. Cancer gene therapies and celltherapies include the insertion of a normal gene into cancer cells toreplace a mutated or altered gene; genetic modification to silence amutated gene; genetic approaches to directly kill the cancer cells;including the infusion of immune cells designed to replace most of thepatient's own immune system to enhance the immune response to cancercells, or activate the patient's own immune system (T cells or NaturalKiller cells) to kill cancer cells, or find and kill the cancer cells;genetic approaches to modify cellular activity to further alterendogenous immune responsiveness against cancer.

Cellular Therapies

In various embodiments, a compound as described herein, is combined withone or more cellular therapies. Illustrative cellular therapies includewithout limitation co-administration of one or more of a population ofnatural killer (NK) cells, NK-T cells, T cells, gamma delta T cells,cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumorinfiltrating lymphocytes (TILs) and/or dendritic cells (DCs). In someembodiments, the cellular therapy entails a T cell therapy, e.g.,co-administering a population of alpha/beta TCR T cells, gamma/delta TCRT cells, regulatory T (Treg) cells and/or TRuC™ T cells. In someembodiments, the cellular therapy entails a NK cell therapy, e.g.,co-administering NK-92 cells. As appropriate, a cellular therapy canentail the co-administration of cells that are autologous, syngeneic orallogeneic to the subject.

In some embodiments, the cellular therapy entails co-administering cellscomprising chimeric antigen receptors (CARs). In such therapies, apopulation of immune effector cells engineered to express a CAR, whereinthe CAR comprises a tumor antigen-binding domain. In T cell therapies,the T cell receptors (TCRs) are engineered to target tumor derivedpeptides presented on the surface of tumor cells.

With respect to the structure of a CAR, in some embodiments, the CARcomprises an antigen binding domain, a transmembrane domain, and anintracellular signaling domain. In some embodiments, the intracellulardomain comprises a primary signaling domain, a costimulatory domain, orboth of a primary signaling domain and a costimulatory domain. In someembodiments, the primary signaling domain comprises a functionalsignaling domain of one or more proteins selected from the groupconsisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcRgamma (FCERIG), FcR beta (Fc Epsilon RIb), CD79a, CD79b, Fcgamma RIIa,DAP10, and DAP12.

In some embodiments, the costimulatory domain comprises a functionaldomain of one or more proteins selected from the group consisting ofCD27, CD28, 4-1BB (CD137), OX40, CD30, CD40, PD-1, ICOS, CD2, CD7,LIGHT, NKG2C, B7-H3, a ligand that specifically binds with CD83, CDS,ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD19, CD4,CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1,CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, ITGAE, CD103,ITGAL, CD1A (NCBI Gene ID: 909), CD1B (NCBI Gene ID: 910), CD1C (NCBIGene ID: 911), CD1D (NCBI Gene ID: 912), CD1E (NCBI Gene ID: 913),ITGAM, ITGAX, ITGB1, CD29, ITGB2 (CD18, LFA-1), ITGB7, TNFR²,TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile),CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69,SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8),SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46,and NKG2D.

In some embodiments, the transmembrane domain comprises a transmembranedomain of a protein selected from the group consisting of the alpha,beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45, CD4,CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137,CD154, KIRDS2, OX40, CD2, CD27, ICOS (CD278), 4-1BB (CD137), GITR, CD40,BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD19, IL2R beta, IL2Rgamma, IL7R, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f,ITGAD, CD1A, CD1B, CD1C, CD1D, CD1E, ITGAE, CD103, ITGAL, ITGAM, ITGAX,ITGB1, CD29, ITGB2 (LFA-1, CD18), ITGB7, TNFR², DNAM1 (CD226), SLAMF4(CD244, 2B4), CD84, CD96 (TACTILE), CEACAM1, CRTAM, Ly9 (CD229), CD160(BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Ly108), SLAM (SLAMF1,CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKp44,NKp30, NKp46, NKG2D, and NKG2C.

In some embodiments, the TCR or CAR antigen binding domain or theimmunotherapeutic agent described herein (e.g., monospecific ormulti-specific antibody or antigen-binding fragment thereof or antibodymimetic) binds a tumor-associated antigen (TAA). In some embodiments,the tumor-associated antigen is selected from the group consisting of:CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1,CRACC, SLAMF7, CD319, and 19A24); C-type lectin-like molecule-1 (CLL-1or CLECLI); CD33; epidermal growth factor receptor variant III(EGFRvlll); ganglioside G2 (GD2); ganglioside GD3(αNeuSAc(2-8)αNeuSAc(2-3)βDGaip(1-4)bDGIcp(1-1)Cer); ganglioside GM3(αNeuSAc(2-3)βDGalp(1-4)(3DG1cp(1-1)Cer); GM-CSF receptor; TNF receptorsuperfamily member 17 (TNFRSF17, BCMA); B-lymphocyte cell adhesionmolecule; Tn antigen ((Tn Ag) or (GaINAcu-Ser/Thr)); prostate-specificmembrane antigen (PSMA); Receptor tyrosine kinase-like orphan receptor 1(RORI); Tumor-associated glycoprotein 72 (TAG72); CD38; CD44v6;Carcinoembryonic antigen (CEA); Epithelial cell adhesion molecule(EPCAM); B7H3 (CD276); KIT (CD117); Interleukin-13 receptor subunitalpha-2 (IL-13Ra2 or CD213A2); Mesothelin; Interleukin 11 receptor alpha(IL-11Ra); prostate stem cell antigen (PSCA); Protease Serine 21(Testisin or PRSS21); vascular endothelial growth factor receptor 2(VEGFR2); HLA class I antigen A-2 alpha; HLA antigen; Lewis(Y)antigen;CD24; Platelet-derived growth factor receptor beta (PDGFR-beta);Stage-specificembryonic antigen-4 (SSEA-4); CD20; delta like 3 (DLL3);Folate receptor alpha; Folate receptor beta, GDNF alpha 4 receptor,Receptor tyrosine-protein kinase, ERBB2 (Her2/neu); Mucin 1, cellsurface associated (MUC1); APRIL receptor; ADP ribosyl cyclase-1; Ephb4tyrosine kinase receptor, DCAMKL1 serine threonine kinase, Aspartatebeta-hydroxylase, epidermal growth factor receptor (EGFR); neural celladhesion molecule (NCAM); Prostase; prostatic acid phosphatase (PAP);elongation factor 2 mutated (ELF2M); Ephrin B2; fibroblast activationprotein alpha (FAP); insulin-like growth factor 1 receptor (IGF-Ireceptor), carbonic anhydrase IX (CAIX); Proteasome (Prosome, Macropain)Subunit, Beta Type, 9 (LMP2); glycoprotein 100 (gp100); oncogene fusionprotein consisting of breakpoint cluster region (BCR) and Abelson murineleukemia viral oncogene homolog 1 (Abl) (bcr-abl); tyrosinase; ephrintype-A receptor 2 (EphA2); ephrin type-A receptor 3 (EphA3), FucosylGM1; sialyl Lewis adhesion molecule (sLe); transglutaminase 5 (TGS5);high molecular weight-melanomaassociatedantigen (HMWMAA); o-acetyl-GD2ganglioside (OAcGD2); Folate receptor beta; tumor endothelial marker 1(TEM1/CD248); tumor endothelial marker 7-related (TEM7R); sixtransmembrane epithelial antigen of the prostate I (STEAP1); claudin 6(CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupledreceptor class C group 5, member D (GPRCSD); IL-15 receptor (IL-15);chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplasticlymphoma kinase (ALK); Polysialic acid; placenta-specific 1 (PLAC1);hexasaccharide portion of globoH glycoceramide (GloboH); mammary glanddifferentiation antigen (NY-BR-1); uroplakin 2 (UPK2); Hepatitis A viruscellular receptor 1 (HAVCR1); adrenoceptor beta 3 (ADRB3); pannexin 3(PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen 6complex, locus K 9 (LY6K); Olfactory receptor 51E2 (ORS IE2); TCR GammaAlternate Reading Frame Protein (TARP); Wilms tumor protein (WT1);Cancer/testis antigen 1 (NY-ESO-1); Cancer/testis antigen 2 (LAGE-1a);Melanoma associated antigen 1 (MAGE-A1); Melanoma associated antigen 3(MAGE-A3); Melanoma associated antigen 4 (MAGE-A4); T cell receptor beta2 chain C; ETS translocation-variant gene 6, located on chromosome 12p(ETV6-AML); sperm protein 17 (SPA17); X Antigen Family, Member lA(XAGE1); angiopoietin-binding cell surface receptor 2 (Tie 2); melanomacancer testis antigen-1 (MADCT-1); melanoma cancer testis antigen-2(MAD-CT-2); Fos-related antigen 1; tumor protein p53, (p53); p53 mutant;prostein; survivin; telomerase; prostate carcinoma tumor antigen-1(PCTA-1 or Galectin 8), melanoma antigen recognized by T cells 1 (MelanAor MARTI); Rat sarcoma (Ras) mutant; human Telomerase reversetranscriptase (hTERT); sarcoma translocation breakpoints; melanomainhibitor of apoptosis (ML-IAP); ERG (transmembrane protease, serine 2(TMPRSS2) ETS fusion gene); N-Acetyl glucosaminyl-transferase V (NA17);paired box protein Pax-3 (PAX3); Androgen receptor; Cyclin-A1; CyclinB1; v-myc avian myelocytomatosis viral oncogene neuroblastoma derivedhomolog (MYCN); Ras Homolog Family Member C (RhoC); Tyrosinase-relatedprotein 2 (TRP-2); Cytochrome P450 1B1 (CYP IBI); CCCTC-Binding Factor(Zinc Finger Protein)-Like (BORIS or Brother of the Regulator ofImprinted Sites), Squamous Cell Carcinoma Antigen Recognized By T Cells3 (SART3); Paired box protein Pax-5 (PAXS); proacrosin binding proteinsp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); Akinase anchor protein 4 (AKAP-4); Peptidoglycan recognition protein,synovial sarcoma, X breakpoint 2 (SSX2); Receptor for Advanced GlycationEndproducts (RAGE-I); renal ubiquitous 1 (RUI); renal ubiquitous 2(RU2); legumain; human papilloma virus E6 (HPV E6); human papillomavirus E7 (HPV E7); intestinal carboxyl esterase; heat shock protein 70-2mutated (mut hsp70-2); CD79a; CD79b; CD72; Leukocyte-associatedimmunoglobulin-like receptor 1 (LAIRI); Fc fragment of IgA receptor(FCAR or CD89); Leukocyte immunoglobulin-like receptor subfamily Amember 2 (LILRA2); CD300 molecule-like family member f (CD300LF); C-typelectin domain family 12 member A (CLEC12A); bone marrow stromal cellantigen 2 (BST2); EGF-like module containing mucin-like hormonereceptor-like 2 (EMR2); lymphocyte antigen 75 (LY75); Glypican-2 (GPC2);Glypican-3 (GPC3); Fc receptor-like 5 (FCRLS); and immunoglobulinlambda-like polypeptide 1 (IGLL1). In some embodiments, the target is anepitope of the tumor associated antigen presented in an MHC.

In some embodiments, the tumor antigen is selected from CD150, 5T4,ActRIIA, B7, TNF receptor superfamily member 17 (TNFRSF17, BCMA),CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20,CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33,CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54,CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-Bfibronectin, EGFR, EGFRvIII, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4,FBP, HER1-HER2 in combination, HER2-HER3 in combination, HERV-K, HIV-1envelope glycoprotein gp120, HIV-1 envelope glycoprotein gp41, HLA-DR,HLA class I antigen alpha G, HM1.24, K-Ras GTPase, HMW-MAA, Her2,Her2/neu, IGF-1R, IL-11Ralpha, IL-13R-alpha2, IL-2, IL-22R-alpha, IL-6,IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, L1-CAM, MAGEA3, MAGE-A1, MART-1, MUC1, NKG2C ligands, NKG2D Ligands, NYESO-1,OEPHa2, PIGF, PSCA, PSMA, ROR1, T101, TAC, TAG72, TIM-3, TRAIL-R1,TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR², WT-I, a G-protein coupledreceptor, alphafetoprotein (AFP), an angiogenesis factor, an exogenouscognate binding molecule (ExoCBM), oncogene product, anti-folatereceptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D 1), ephrinB2,epithelial tumor antigen, estrogen receptor, fetal acetylcholine ereceptor, folate binding protein, gp100, hepatitis B surface antigen,Epstein-Barr nuclear antigen 1, Latent membrane protein 1, Secretedprotein BARF1, P2X7 purinoceptor, Syndecan-1, kappa chain, kappa lightchain, kdr, lambda chain, livin, melanoma-associated antigen,mesothelin, mouse double minute 2 homolog (MDM2), mucin 16 (MUC16),mutated p53, mutated ras, necrosis antigens, oncofetal antigen, ROR²,progesterone receptor, prostate specific antigen, tEGFR, tenascin,P2-Microgiobuiin, Fc Receptor-like 5 (FcRL5).

Examples of cell therapies include without limitation: AMG-119,Algenpantucel-L, ALOFISEL®, Sipuleucel-T, (BPX-501) rivogenlecleucelU.S. Pat. No. 9,089,520, WO2016100236, AU-105, ACTR-087, activatedallogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601,FATE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T,baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190,CD19-ARTEMIS, ProHema, FT-1050-treated bone marrow stem cell therapy,CD4CARNK-92 cells, SNK-01, NEXI-001, CryoStim, AlloStim, lentiviraltransduced huCART-meso cells, CART-22 cells, EGFRt/19-28z/4-1BBL CAR Tcells, autologous 4H11-28z/fIL-12/EFGRt T cell, CCR5-SBC-728-HSPC,CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL-12, IMA-101,IMA-201, CARMA-0508, TT-18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601,CMD-602, CSG-005, LAAP T-cell therapy, PD-1 knockout T cell therapy(esophageal cancer/NSCLC), anti-MUC1 CAR T-cell therapy (esophagealcancer/NSCLC), anti-MUC1 CAR T-cell therapy+PD-1 knockout T cell therapy(esophageal cancer/NSCLC), anti-KRAS G12D mTCR PBL, anti-CD123 CART-cell therapy, anti-mutated neoantigen TCR T-cell therapy, tumorlysate/MUC1/survivin PepTivator-loaded dendritic cell vaccine,autologous dendritic cell vaccine (metastatic malignant melanoma,intradermal/intravenous), anti-LeY-scFv-CD28-zeta CAR T-cells,PRGN-3005, iC9-GD2-CAR-IL-15 T-cells, HSC-100, ATL-DC-101, MIDRIX4-LUNG,MIDRIXNEO, anti-CD20 CAR T-cell therapy (non-Hodgkin's lymphoma),

Additional Agents for Targeting Tumors Include without Limitation:

-   -   Alpha-fetoprotein modulators, such as ET-1402, and AFP-TCR;    -   Anthrax toxin receptor 1 modulator, such as anti-TEM8 CAR T-cell        therapy;    -   TNF receptor superfamily member 17 (TNFRSF17, BCMA), such as        bb-2121 (ide-cel), bb-21217, JCARH125, UCART-BCMA, ET-140,        KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212,        ET-140, P-BCMA-101, AUTO-2 (APRIL-CAR), JNJ-68284528;    -   Anti-CLL-1 antibodies, such as KITE-796;    -   Anti-PD-L1-CAR tank cell therapy, such as KD-045    -   Anti-PD-L1 t-haNK, such as PD-L1 t-haNK;    -   anti-CD45 antibodies, such as 131I-BC8 (lomab-B);    -   anti-HER3 antibodies, such as LJM716, GSK2849330;    -   anti-CD52 antibodies, such as alemtuzumab;    -   APRIL receptor modulator, such as anti-BCMA CAR T-cell therapy,        Descartes-011;    -   ADP ribosyl cyclase-1/APRIL receptor modulator, such as dual        anti-BCMA/anti-CD38 CAR T-cell therapy; CART-ddBCMA;    -   B7 homolog 6, such as CAR-NKp30 and CAR-B7H6;    -   B-lymphocyte antigen CD19, such as TBI-1501, CTL-119 huCART-19 T        cells, 1 iso-cel, JCAR-015 U.S. Pat. No. 7,446,190, JCAR-014,        JCAR-017, (WO2016196388, WO2016033570, WO2015157386),        axicabtagene ciloleucel (KTE-C19, Yescarta®), KTE-X19, U.S. Pat.        Nos. 7,741,465, 6,319,494, UCART-19, EBV-CTL, T        tisagenlecleucel-T (CTL019), WO2012079000, WO2017049166,        CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells, CD19/4-1BBL        armored CAR T cell therapy, C-CAR-011, CIK-CAR.CD19,        CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01, IM19        CAR-T, TC-110; anti-CD19 CAR T-cell therapy (B-cell acute        lymphoblastic leukemia, Universiti Kebangsaan Malaysia);        anti-CD19 CAR T-cell therapy (acute lymphoblastic        leukemia/Non-Hodgkin's lymphoma, University Hospital        Heidelberg), anti-CD19 CAR T-cell therapy (silenced IL-6        expression, cancer, Shanghai Unicar-Therapy Bio-medicine        Technology), MB-CART2019.1 (CD19/CD20), GC-197 (CD19/CD7),        CLIC-1901, ET-019003, anti-CD19-STAR-T cells, AVA-001, BCMA-CD19        cCAR (CD19/APRIL), ICG-134, ICG-132 (CD19/CD20), CTA-101,        WZTL-002, dual anti-CD19/anti-CD20 CAR T-cells (chronic        lymphocytic leukemia/B-cell lymphomas), HY-001, ET-019002,        YTB-323, GC-012 (CD19/APRIL), GC-022 (CD19/CD22),        CD19CAR-CD28-CD3zeta-EGFRt-expres sing Tn/mem; UCAR-011,        ICTCAR-014, GC-007F, PTG-01, CC-97540;    -   Allogeneic anti-CD19 CART cells, such as GC-007G;    -   APRIL receptor modulator; SLAM family member 7 modulator,        BCMA-CS1 cCAR;    -   Autologous dendritic cell tumor antigen (ADCTA), such as        ADCTA-SSI-G;    -   B-lymphocyte antigen CD20, such as ACTR707 ATTCK-20, PBCAR-20A;    -   Allogenic T cells expressing CD20 CAR, such as LB-1905;    -   B-lymphocyte antigen CD19/B-lymphocyte antigen 22, such as        TC-310;    -   B-lymphocyte antigen 22 cell adhesion, such as UCART-22,        JCAR-018 WO2016090190;    -   NY-ESO-1 modulators, such as GSK-3377794, TBI-1301, GSK3537142;    -   Carbonic anhydrase, such as DC-Ad-GMCAIX;    -   Caspase 9 suicide gene, such as CaspaClDe DLI, BPX-501;    -   CCR5, such as SB-728;    -   CCR5 gene inhibitor/TAT gene/TRIM5 gene stimulator, such as        lentivirus vector CCR5 shRNA/TRIM5alpha/TAR decoy-transduced        autologous CD34-positive hematopoietic progenitor cells;    -   CDw123, such as MB-102, IM-23, JEZ-567, UCART-123;    -   CD4, such as ICG-122;    -   CD5 modulators, such as CD5.28z CART cells;    -   Anti-CD22, such as anti-CD22 CART;    -   Anti-CD30, such as TT-11;    -   CD33, such as CIK-CAR.CD33, CD33CART;    -   Dual anti-CD33/anti-CLL1, such as LB-1910;    -   CD38, such as T-007, UCART-38;    -   CD40 ligand, such as BPX-201, MEDI5083;    -   CD56, such as allogeneic CD56-positive CD3-negative natural        killer cells (myeloid malignancies);    -   CD19/CD7 modulator, such as GC-197;    -   T-cell antigen CD7 modulator, such as anti-CD7 CAR T-cell        therapy (CD7-positive hematological malignancies);    -   CD123 modulator, such as UniCAR02-T-CD123;    -   CEACAM protein 5 modulators, such as MG7-CART;    -   Claudin 6, such as CSG-002;    -   Claudin 18.2, such as LB-1904;    -   Chlorotoxin, such as CLTX-CART;    -   EBV targeted, such as CMD-003;    -   MUC16EGFR, such as autologous 4H11-28z/fIL-12/EFGRt T cell;    -   Endonuclease, such as PGN-514, PGN-201;    -   Epstein-Barr virus specific T-lymphocytes, such as TT-10;    -   Epstein-Barr nuclear antigen 1/Latent membrane protein        1/Secreted protein BARF1 modulator, such as TT-10X;    -   Erbb2, such as CST-102, CIDeCAR;    -   Ganglioside (GD2), such as 4SCAR-GD2;    -   Gamma delta T cells, such as ICS-200;    -   folate hydrolase 1 (FOLH1, Glutamate carboxypeptidase II, PSMA;        NCBI Gene ID: 2346), such as CIK-CAR.PSMA, CART-PSMA-TGFβRDN,        P-PSMA-101;    -   Glypican-3 (GPC3), such as TT-16, GLYCAR;    -   Hemoglobin, such as PGN-236;    -   Hepatocyte growth factor receptor, such as anti-cMet RNA CAR T;    -   HLA class I antigen A-2 alpha modulator, such as FH-MCVA2TCR;    -   HLA class I antigen A-2 alpha/Melanoma associated antigen 4        modulator, such as ADP-A2M4CD8;    -   HLA antigen modulator, such as FIT-001, NeoTCR-P1;    -   Human papillomavirus E7 protein, such as KITE-439;    -   ICAM-1 modulator, such as AIC-100;    -   Immunoglobulin gamma Fc receptor III, such as ACTR087;    -   IL-12, such as DC-RTS-IL-12;    -   IL-12 agonist/mucin 16, such as JCAR-020;    -   IL-13 alpha 2, such as MB-101;    -   IL-15 receptor agonist, such as PRGN-3006;    -   IL-2, such as CST-101;    -   Interferon alpha ligand, such as autologous tumor cell        vaccine+systemic CpG-B+IFN-alpha (cancer);    -   K-Ras GTPase, such as anti-KRAS G12V mTCR cell therapy;    -   Neural cell adhesion molecule L1 L1CAM (CD171), such as        JCAR-023;    -   Latent membrane protein 1/Latent membrane protein 2, such as        Ad5f35-LMPd1-2-transduced autologous dendritic cells;    -   MART-1 melanoma antigen modulator, such as MART-1 F5 TCR        engineered PBMC;    -   Melanoma associated antigen 10, such as MAGE-A10C796T MAGE-A10        TCR;    -   Melanoma associated antigen 3/Melanoma associated antigen 6        (MAGE A3/A6) such as KITE-718;    -   Mesothelin, such as CSG-MESO, TC-210;    -   Mucin 1 modulator, such as ICTCAR-052, Tn MUC-1 CAR-T,        ICTCAR-053;    -   Anti-MICA/MICB, such as CYAD-02;    -   NKG2D, such as NKR-2;    -   Ntrkrl tyrosine kinase receptor, such as JCAR-024;    -   PRAMET cell receptor, such as BPX-701;    -   Prostate stem cell antigen modulator, such as MB-105;    -   Roundabout homolog 1 modulator, such as ATCG-427;    -   Peptidoglycan recognition protein modulator, such as Tag-7 gene        modified autologous tumor cell vaccine;    -   PSMA, such as PSMA-CAR T-cell therapy (lentiviral vector,        castrate-resistant prostate cancer)    -   SLAM family member 7 modulator, such as IC9-Luc90-CD828Z;    -   TGF beta receptor modulator, such as DNR.NPC T-cells;    -   T-lymphocyte, such as TT-12;    -   T-lymphocyte stimulator, such as ATL-001;    -   TSH receptor modulator, such as ICTCAR-051;    -   Tumor infiltrating lymphocytes, such as LN-144, LN-145;    -   Wilms tumor protein, such as JTCR-016, WT1-CTL, ASP-7517;

Gene Editors

In various embodiments, a compound as described herein, is combined withgene editor. Illustrative gene editing system that can beco-administered include without limitation a CRISPR/Cas9 system, a zincfinger nuclease system, a TALEN system, a homing endonucleases system(e.g., an ARCUS), and a homing meganuclease system.

Other Targets

In various embodiments, a compound as described herein, is combined withhuman immunoglobulin (10% liquid formulation), Cuvitru (humanimmunoglobulin (20% solution), levofolinate disodium, IMSA-101,BMS-986288, IMUNO BGC Moreau RJ, R-OKY-034F, GP-2250, AR-23, calciumlevofolinate, porfimer sodium, RG6160, ABBV-155, CC-99282, polifeprosan20 with carmustine, Veregen, gadoxetate disodium, gadobutrol, gadoteratemeglumine, gadoteridol, 99mTc-sestamibi, pomalidomide, pacibanil,valrubicin,

Exemplified Combination Therapies Lymphoma or Leukemia CombinationTherapy

Some chemotherapy agents are suitable for treating lymphoma or leukemia.These agents include aldesleukin, alvocidib, amifostine trihydrate,aminocamptothecin, antineoplaston A10, antineoplaston AS2-1,anti-thymocyte globulin, arsenic trioxide, Bcl-2 family proteininhibitor ABT-263, beta alethine, BMS-345541bortezomib (VELCADE®,PS-341), bryostatin 1, bulsulfan, campath-1H, carboplatin, carfilzomib(Kyprolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil,CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone),cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide,vincristine, and prednisone), cyclophosphamide, cyclosporine,cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone,thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide),enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), FCM(fludarabine, cyclophosphamide, and mitoxantrone), FCR (fludarabine,cyclophosphamide, and rituximab), fenretinide, filgrastim, flavopiridol,fludarabine, FR (fludarabine and rituximab), geldanamycin (17 AAG),hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin,dexamethasone, methotrexate, and cytarabine), ICE (iphosphamide,carboplatin, and etoposide), ifosfamide, irinotecan hydrochloride,interferon alpha-2b, ixabepilone, lenalidomide (REVLIMID®, CC-5013),pomalidomide (POMALYST®/IMNOVID®) lymphokine-activated killer cells, MCP(mitoxantrone, chlorambucil, and prednisolone), melphalan, mesna,methotrexate, mitoxantrone hydrochloride, motexafin gadolinium,mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen,octreotide acetate, omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix),oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim,PEGylated liposomal doxorubicin hydrochloride, perifosin, prednisolone,prednisone, recombinant flt3 ligand, recombinant human thrombopoietin,recombinant interferon alfa, recombinant interleukin-11, recombinantinterleukin-12, rituximab, R—CHOP (rituximab and CHOP), R-CVP (rituximaband CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and RMCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202),sargramostim, sildenafil citrate, simvastatin, sirolimus, styrylsulphones, tacrolimus, tanespimycin, temsirolimus (CC₁₋₇₇₉),thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib,vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA(suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid),vemurafenib (Zelboraf C)), venetoclax (ABT-199).

One modified approach is radioimmunotherapy, wherein a monoclonalantibody is combined with a radioisotope particle, such as indium-111,yttrium-90, and iodine-131. Examples of combination therapies include,but are not limited to, iodine-131 tositumomab (BEXXAR®), yttrium-90ibritumomab tiuxetan (ZEVALIN®), and BEXXAR® with CHOP.

The abovementioned therapies can be supplemented or combined with stemcell transplantation or treatment. Therapeutic procedures includeperipheral blood stem cell transplantation, autologous hematopoieticstem cell transplantation, autologous bone marrow transplantation,antibody therapy, biological therapy, enzyme inhibitor therapy, totalbody irradiation, infusion of stem cells, bone marrow ablation with stemcell support, in vitro-treated peripheral blood stem celltransplantation, umbilical cord blood transplantation, immunoenzymetechnique, low-LET cobalt-60 gamma ray therapy, bleomycin, conventionalsurgery, radiation therapy, and nonmyeloablative allogeneichematopoietic stem cell transplantation.

Non-Hodgkin's Lymphomas Combination Therapy

Treatment of non-Hodgkin's lymphomas (NHL), especially those of B cellorigin, includes using monoclonal antibodies, standard chemotherapyapproaches (e.g., CHOP (cyclophosphamide, doxorubicin, vincristine, andprednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM(fludarabine, cyclophosphamide, and mitoxantrone), MCP (Mitoxantrone,Chlorambucil, Prednisolone), all optionally including rituximab (R) andthe like), radioimmunotherapy, and combinations thereof, especiallyintegration of an antibody therapy with chemotherapy.

Examples of unconjugated monoclonal antibodies for the treatment ofNHL/B-cell cancers include rituximab, alemtuzumab, human or humanizedanti-CD20 antibodies, lumiliximab, anti-TNF-related apoptosis-inducingligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN-40, andanti-CD74.

Examples of experimental antibody agents used in treatment of NHL/B-cellcancers include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab,SGN-40, CHIR-12.12, epratuzumab, lumiliximab, apolizumab, milatuzumab,and bevacizumab.

Examples of standard regimens of chemotherapy for NHL/B-cell cancersinclude CHOP, FCM, CVP, MCP, R—CHOP (rituximab, cyclophosphamide,doxorubicin, vincristine, and prednisone), R-FCM, R-CVP, and R MCP.

Examples of radioimmunotherapy for NHL/B-cell cancers include yttrium-90ibritumomab tiuxetan (ZEVALIN®) and iodine-131 tositumomab (BEXXAR®).

Mantle Cell Lymphoma Combination Therapy

Therapeutic treatments for mantle cell lymphoma (MCL) includecombination chemotherapies such as CHOP, hyperCVAD, and FCM. Theseregimens can also be supplemented with the monoclonal antibody rituximabto form combination therapies R—CHOP, hyperCVAD-R, and R-FCM. Any of theabovementioned therapies may be combined with stem cell transplantationor ICE in order to treat MCL.

An alternative approach to treating MCL is immunotherapy. Oneimmunotherapy uses monoclonal antibodies like rituximab. Another usescancer vaccines, such as GTOP-99, which are based on the genetic makeupof an individual patient's tumor.

A modified approach to treat MCL is radioimmunotherapy, wherein amonoclonal antibody is combined with a radioisotope particle, such asiodine-131 tositumomab (BEXXAR®) and yttrium-90 ibritumomab tiuxetan(ZEVALIN®). In another example, BEXXAR® is used in sequential treatmentwith CHOP.

Other approaches to treating MCL include autologous stem celltransplantation coupled with high-dose chemotherapy, administeringproteasome inhibitors such as bortezomib (VELCADE® or PS-341), oradministering antiangiogenesis agents such as thalidomide, especially incombination with rituximab.

Another treatment approach is administering drugs that lead to thedegradation of Bcl-2 protein and increase cancer cell sensitivity tochemotherapy, such as oblimersen, in combination with otherchemotherapeutic agents.

A further treatment approach includes administering mTOR inhibitors,which can lead to inhibition of cell growth and even cell death.Non-limiting examples are sirolimus, temsirolimus (TORISEL®, CCI-779),CC-115, CC-223, SF-1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458,and temsirolimus in combination with RITUXAN®, VELCADE®, or otherchemotherapeutic agents.

Other recent therapies for MCL have been disclosed. Such examplesinclude flavopiridol, palbociclib (PD0332991), R-roscovitine(selicicilib, CYC202), styryl sulphones, obatoclax (GX15-070), TRAIL,Anti-TRAIL death receptors DR4 and DR5 antibodies, temsirolimus(TORISEL®, CC₁₋₇₇₉), everolimus (RAD001), BMS-345541, curcumin, SAHA,thalidomide, lenalidomide (REVLIMID®, CC-5013), and geldanamycin (17AAG).

Waldenstrom's Macroglobulinemia Combination Therapy

Therapeutic agents used to treat Waldenstrom's Macroglobulinemia (WM)include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate,aminocamptothecin, antineoplaston A10, antineoplaston AS2-1,anti-thymocyte globulin, arsenic trioxide, autologous humantumor-derived HSPPC-96, Bcl-2 family protein inhibitor ABT-263, betaalethine, bortezomib (VELCADE®), bryostatin 1, busulfan, campath-1H,carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin,clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukindiftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicinhydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab(hLL2-anti-CD22 humanized antibody), etoposide, everolimus, fenretinide,filgrastim, fludarabine, ibrutinib, ifosfamide, indium-111 monoclonalantibody MN-14, iodine-131 tositumomab, irinotecan hydrochloride,ixabepilone, lymphokine-activated killer cells, melphalan, mesna,methotrexate, mitoxantrone hydrochloride, monoclonal antibody CD19 (suchas tisagenlecleucel-T, CART-19, CTL-019), monoclonal antibody CD20,motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen,octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel,pegfilgrastim, PEGylated liposomal doxorubicin hydrochloride,pentostatin, perifosine, prednisone, recombinant flt3 ligand,recombinant human thrombopoietin, recombinant interferon alfa,recombinant interleukin-11, recombinant interleukin-12, rituximab,sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus,tacrolimus, tanespimycin, thalidomide, therapeutic allogeneiclymphocytes, thiotepa, tipifarnib, tositumomab, ulocuplumab, veltuzumab,vincristine sulfate, vinorelbine ditartrate, vorinostat, WT1 126-134peptide vaccine, WT-1 analog peptide vaccine, yttrium-90 ibritumomabtiuxetan, yttrium-90 humanized epratuzumab, and any combination thereof.

Examples of therapeutic procedures used to treat WM include peripheralblood stem cell transplantation, autologous hematopoietic stem celltransplantation, autologous bone marrow transplantation, antibodytherapy, biological therapy, enzyme inhibitor therapy, total bodyirradiation, infusion of stem cells, bone marrow ablation with stem cellsupport, in vitro-treated peripheral blood stem cell transplantation,umbilical cord blood transplantation, immunoenzyme techniques, low-LETcobalt-60 gamma ray therapy, bleomycin, conventional surgery, radiationtherapy, and nonmyeloablative allogeneic hematopoietic stem celltransplantation.

Diffuse Large B-Cell Lymphoma Combination Therapy

Therapeutic agents used to treat diffuse large B-cell lymphoma (DLBCL)include cyclophosphamide, doxorubicin, vincristine, prednisone,anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of theagents listed for WM, and any combination thereof, such as ICE and RICE.

Chronic Lymphocytic Leukemia Combination Therapy

Examples of therapeutic agents used to treat chronic lymphocyticleukemia (CLL) include chlorambucil, cyclophosphamide, fludarabine,pentostatin, cladribine, doxorubicin, vincristine, prednisone,prednisolone, alemtuzumab, many of the agents listed for WM, andcombination chemotherapy and chemoimmunotherapy, including the followingcommon combination regimens: CVP, R-CVP, ICE, R-ICE, FCR, and FR.

Myelofibrosis Combination Therapy

Myelofibrosis inhibiting agents include, but are not limited to,hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosinekinase inhibitors. Non-limiting examples of hedgehog inhibitors aresaridegib and vismodegib. Examples of HDAC inhibitors include, but arenot limited to, pracinostat and panobinostat. Non-limiting examples oftyrosine kinase inhibitors are lestaurtinib, bosutinib, imatinib,radotinib, and cabozantinib.

Hyperproliferative Disorder Combination Therapy

Gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel may be usedwith a JAK inhibitor and/or PI3K6 inhibitor to treat hyperproliferativedisorders.

Bladder Cancer Combination Therapy

Therapeutic agents used to treat bladder cancer include atezolizumab,carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU),gemcitabine, idosfamide, Interferon alfa-2b, methotrexate, mitomycin,nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine, and anycombination thereof.

Breast Cancer Combination Therapy

Therapeutic agents used to treat breast cancer include albumin-boundpaclitaxel, anastrozole, capecitabine, carboplatin, cisplatin,cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus,exemestane, fluorouracil, fulvestrant, gemcitabine, Ixabepilone,lapatinib, Letrozole, methotrexate, mitoxantrone, paclitaxel, pegylatedliposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab,vinorelbine, and any combinations thereof.

Triple Negative Breast Cancer Combination Therapy

Therapeutic agents used to treat triple negative breast cancer includecyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil,paclitaxel, and combinations thereof.

Colorectal Cancer Combination Therapy

Therapeutic agents used to treat colorectal cancer include bevacizumab,capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin,oxaliplatin, panitumumab, ziv-aflibercept, and any combinations thereof.

Castration-Resistant Prostate Cancer Combination Therapy

Therapeutic agents used to treat castration-resistant prostate cancerinclude abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone,sipuleucel-T, and any combinations thereof.

Esophageal and Esophagogastric Junction Cancer Combination Therapy

Therapeutic agents used to treat esophageal and esophagogastric junctioncancer include capecitabine, carboplatin, cisplatin, docetaxel,epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin,oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combinationsthereof.

Gastric Cancer Combination Therapy

Therapeutic agents used to treat gastric cancer include capecitabine,carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine,fluorouracil, Irinotecan, leucovorin, mitomycin, oxaliplatin,paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Head and Neck Cancer Combination Therapy

Therapeutic agents used to treat head & neck cancer include afatinib,bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel,fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab,paclitaxel, pembrolizumab, vinorelbine, and any combinations thereof.

Hepatobiliary Cancer Combination Therapy

Therapeutic agents used to treat hepatobiliary cancer includecapecitabine, cisplatin, fluoropyrimidine, 5-fluorourcil, gemecitabine,oxaliplatin, sorafenib, and any combinations thereof.

Hepatocellular Carcinoma Combination Therapy

Therapeutic agents used to treat hepatocellular carcinoma includecapecitabine, doxorubicin, gemcitabine, sorafenib, and any combinationsthereof.

Non-Small Cell Lung Cancer Combination Therapy

Therapeutic agents used to treat non-small cell lung cancer (NSCLC)include afatinib, albumin-bound paclitaxel, alectinib, bevacizumab,bevacizumab biosimilar, cabozantinib, carboplatin, cisplatin,crizotinib, dabrafenib, docetaxel, erlotinib, etoposide, gemcitabine,nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab,trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine,vinorelbine, and any combinations thereof.

Small Cell Lung Cancer Combination Therapy

Therapeutic agents used to treat small cell lung cancer (SCLC) includebendamustime, carboplatin, cisplatin, cyclophosphamide, docetaxel,doxorubicin, etoposide, gemcitabine, ipillimumab, irinotecan, nivolumab,paclitaxel, temozolomide, topotecan, vincristine, vinorelbine, and anycombinations thereof.

Melanoma Combination Therapy

Therapeutic agents used to treat melanoma cancer include albumin boundpaclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib,dacrabazine, IL-2, imatinib, interferon alfa-2b, ipilimumab,nitrosourea, nivolumab, paclitaxel, pembrolizumab, pilimumab,temozolomide, trametinib, vemurafenib, vinblastine, and any combinationsthereof.

Ovarian Cancer Combination Therapy

Therapeutic agents used to treat ovarian cancer include 5-flourouracil,albumin bound paclitaxel, altretamine, anastrozole, bevacizumab,capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel,doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide, irinotecan,letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate,melphalan, olaparib, oxaliplatin, paclitaxel, Pazopanib, pemetrexed,tamoxifen, topotecan, vinorelbine, and any combinations thereof.

Pancreatic Cancer Combination Therapy

Therapeutic agents used to treat pancreatic cancer include5-fluorourcil, albumin-bound paclitaxel, capecitabine, cisplatin,docetaxel, erlotinib, fluoropyrimidine, gemcitabine, irinotecan,leucovorin, oxaliplatin, paclitaxel, and any combinations thereof.

Renal Cell Carcinoma Combination Therapy

Therapeutic agents used to treat renal cell carcinoma include axitinib,bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab,pazopanib, sorafenib, sunitinib, temsirolimus, and any combinationsthereof.

VI. Methods of Treatment

In some embodiments, the present disclosure provides method ofinhibiting CD73 in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of the present disclosure, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of the present disclosure.In some embodiments, the present disclosure provides method ofinhibiting CD73 in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (I), (II-a), (II-b), (II-c), (II-d), (II-e), (II-f),(II-g), (II-h), (III-a), (III-b), (III-c), or (III-d), or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of the present disclosure.

In some embodiments, the present disclosure provides method of treatingcancer in a subject in need thereof, the method comprising administeringto the subject a therapeutically effective amount of a compound of thepresent disclosure, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of the present disclosure. In someembodiments, the present disclosure provides method of treating cancerin a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of Formula (I),(II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h), (III-a),(III-b), (III-c), or (III-d), or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition of the present disclosure.

In some embodiments, the cancer is pancreatic cancer, bladder cancer,colorectal cancer, breast cancer, prostate cancer, renal cancer,hepatocellular cancer, lung cancer, ovarian cancer, cervical cancer,gastric cancer, esophageal cancer, head and neck cancer, melanoma,neuroendocrine cancer, CNS cancer, brain cancer, bone cancer, softtissue sarcoma, non-small cell lung cancer, small-cell lung cancer,thyroid cancer or colon cancer. In some embodiments, the cancer is acutelymphocytic leukemia (ALL), acute myeloid leukemia (AML), chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL),myelodysplastic syndrome (MDS), myeloproliferative disease (MPD),chronic myeloid leukemia (CML), multiple myeloma (MM), non-Hodgkin'slymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma,Waldestrom's macroglobulinemia (WM), T-cell lymphoma, B-cell lymphoma ordiffuse large B-cell lymphoma (DLBCL). In some embodiments, the canceris brain (gliomas), glioblastomas, astrocytomas, glioblastomamultiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclosdisease, breast, colon, head and neck, kidney, lung, liver, melanoma,ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma,adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma,prostate, sarcoma or thyroid.

In some embodiments, the cancer is a solid tumor, a hematologicalcancer, or a metastatic lesion. In some embodiments, the solid tumor isa sarcoma, a fibroblastic sarcoma, a carcinoma, or an adenocarcinoma. Insome embodiments, the hematological cancer is a leukemia, a lymphoma, ora myeloma.

In some embodiments, the cancer is a lung cancer, a melanoma, a renalcancer, a liver cancer, a myeloma, a prostate cancer, a breast cancer,an ovarian cancer, a colorectal cancer, a pancreatic cancer, a head andneck cancer, an anal cancer, a gastro-esophageal cancer, a mesothelioma,a nasopharyngeal cancer, a thyroid cancer, a cervical cancer, anepithelial cancer, a peritoneal cancer, a lymphoproliferative disease,an acute lymphoblastic leukemia (ALL), an acute myelogenous leukemia(AML), a chronic lymphocytic leukemia (CLL), a chronic myelogenousleukemia (CML), a chronic myelomonocytic leukemia (CMML), a hairy cellleukemia, a B cell lymphoma, a diffuse large B-cell lymphoma (DLBCL), anactivated B-cell like (ABC) diffuse large B cell lymphoma, a germinalcenter B cell (GCB) diffuse large B cell lymphoma, a mantle celllymphoma, a Hodgkin lymphoma, a non-Hodgkin lymphoma, a relapsednon-Hodgkin lymphoma, a refractory non-Hodgkin lymphoma, a recurrentfollicular non-Hodgkin lymphoma, a Burkitt lymphoma, a small lymphocyticlymphoma, a follicular lymphoma, a lymphoplasmacytic lymphoma, or anextranodal marginal zone lymphoma.

In some embodiments, the cancer is an epithelial tumor (e.g., acarcinoma, a squamous cell carcinoma, a basal cell carcinoma, a squamousintraepithelial neoplasia), a glandular tumor (e.g., an adenocarcinoma,an adenoma, an adenomyoma), a mesenchymal or soft tissue tumor (e.g., asarcoma, a rhabdomyosarcoma, a leiomyosarcoma, a liposarcoma, afibrosarcoma, a dermatofibrosarcoma, a neurofibrosarcoma, a fibroushistiocytoma, an angiosarcoma, an angiomyxoma, a leiomyoma, a chondroma,a chondrosarcoma, an alveolar soft-part sarcoma, an epithelioidhemangioendothelioma, a Spitz tumor, a synovial sarcoma), or a lymphoma.

In some embodiments, the cancer is a solid tumor in or arising from atissue or organ selected from the group consisting of: bone (e.g.,adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma,chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma,dedifferentiated chondrosarcoma, enchondroma, epithelioidhemangioendothelioma, fibrous dysplasia of the bone, giant cell tumourof bone, haemangiomas and related lesions, osteoblastoma,osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periostealchondroma, Desmoid tumor, Ewing sarcoma); lips and oral cavity (e.g.,odontogenic ameloblastoma, oral leukoplakia, oral squamous cellcarcinoma, primary oral mucosal melanoma); salivary glands (e.g.,pleomorphic salivary gland adenoma, salivary gland adenoid cysticcarcinoma, salivary gland mucoepidermoid carcinoma, salivary glandWarthin's tumors); esophagus (e.g., Barrett's esophagus, dysplasia andadenocarcinoma); gastrointestinal tract, including stomach (e.g.,gastric adenocarcinoma, primary gastric lymphoma, gastrointestinalstromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastricsarcomas, neuroendocrine carcinoma, gastric primary squamous cellcarcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g.,intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma),rectum, anus; pancreas (e.g., serous neoplasms, including microcystic ormacrocystic serous cystadenoma, solid serous cystadenoma, VonHippel-Landau (VHL)-associated serous cystic neoplasm, serouscystadenocarcinoma, mucinous cystic neoplasms (MCN), intraductalpapillary mucinous neoplasms (IPMN), intraductal oncocytic papillaryneoplasms (IOPN), intraductal tubular neoplasms, cystic acinarneoplasms, including acinar cell cystadenoma, acinar cellcystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreaticductal adenocarcinomas, including tubular adenocarcinoma, adenosquamouscarcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma,signet ring cell carcinoma, undifferentiated carcinoma, undifferentiatedcarcinoma with osteoclast-like giant cells, acinar cell carcinoma,neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrinetumors (NET), neuroendocrine carcinoma (NEC), including small cell orlarge cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producingNET, somatostatinoma, VlPoma, solid-pseudopapillary neoplasms (SPN),pancreatoblastoma); gall bladder (e.g. carcinoma of the gallbladder andextrahepatic bile ducts, intrahepatic cholangiocarcinoma);neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors,phaeochromocytoma, pituitary adenomas); thyroid (e.g., anaplastic(undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors,papillary carcinoma, adenocarcinoma); liver (e.g., adenoma, combinedhepatocellular and cholangiocarcinoma, fibrolamellar carcinoma,hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromalepithelial tumor, undifferentiated carcinoma, hepatocellular carcinoma,intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma,epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma,rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor,carcinosarcoma, rhabdoid tumor); kidney (e.g., ALK-rearranged renal cellcarcinoma, chromophobe renal cell carcinoma, clear cell renal cellcarcinoma, clear cell sarcoma, metanephric adenoma, metanephricadenofibroma, mucinous tubular and spindle cell carcinoma, nephroma,nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cellcarcinoma, renal oncocytoma, renal cell carcinoma, succinatedehydrogenase-deficient renal cell carcinoma, collecting ductcarcinoma); breast (e.g., invasive ductal carcinoma, including withoutlimitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrinecarcinoma, cribriform carcinoma, glycogen-rich/clear cell, inflammatorycarcinoma, lipid-rich carcinoma, medullary carcinoma, metaplasticcarcinoma, micropapillary carcinoma, mucinous carcinoma, neuroendocrinecarcinoma, oncocytic carcinoma, papillary carcinoma, sebaceouscarcinoma, secretory breast carcinoma, tubular carcinoma, lobularcarcinoma, including without limitation, pleomorphic carcinoma, signetring cell carcinoma, peritoneum (e.g., mesothelioma, primary peritonealcancer)); female sex organ tissues, including ovary (e.g.,choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromaltumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinousadenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma,transitional cell carcinoma, squamous cell carcinoma, undifferentiatedcarcinoma, mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma,germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g.,carcinoma of the cervix, endometrial polyps, endometrial hyperplasia,intraepithelial carcinoma (EIC), endometrial carcinoma (e.g.,endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinouscarcinoma, squamous cell carcinoma, transitional carcinoma, small cellcarcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma(e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromalsarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymaltumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma(malignant mixed mesodermal sarcoma—MMMT)), endometrial stromal tumors,endometrial malignant mullerian mixed tumours, gestational trophoblastictumors (partial hydatiform mole, complete hydatiform mole, invasivehydatiform mole, placental site tumour)), vulva, vagina; male sex organtissues, including prostate, testis (e.g., germ cell tumors,spermatocytic seminoma), penis; bladder (e.g., squamous cell carcinoma,urothelial carcinoma, bladder urothelial carcinoma); brain, (e.g.,gliomas (e.g., astrocytomas, including non-infiltrating, low-grade,anaplastic, glioblastomas; oligodendrogliomas, ependymomas),meningiomas, gangliogliomas, schwannomas (neurilemmomas),craniopharyngiomas, chordomas, Non-Hodgkin lymphomas, pituitary tumors;eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uvealmelanoma, iris hamartoma); head and neck (e.g., nasopharyngealcarcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma,laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glotticcarcinoma, supraglottic carcinoma, subglottic carcinoma, transglotticcarcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC,undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cysticcarcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neckparagangliomas (e.g., carotid body, jugulotympanic, vagal); thymus(e.g., thymoma); heart (e.g., cardiac myxoma); lung (e.g., small cellcarcinoma (SCLC), non-small cell lung carcinoma (NSCLC), includingsquamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma,carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas,giant cell carcinomas, spindle cell carcinomas, pleuropulmonaryblastoma); lymph (e.g., lymphomas, including Hodgkin's lymphoma,non-Hodgkin's lymphoma, Epstein-Barr virus (EBV)-associatedlymphoproliferative diseases, including B cell lymphomas and T celllymphomas (e.g., Burkitt lymphoma, large B cell lymphoma, diffuse largeB-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma,low grade B cell lymphoma, fibrin-associated diffuse large celllymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodalNK/T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous Tcell lymphoma, angioimmunoblastic T cell lymphoma; follicular T celllymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis); centralnervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g.,pilocytic astrocytoma, pilomyxoid astrocytoma, subependymal giant cellastrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma,fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmicastrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cellglioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosiscerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplasticoligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma,anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom,myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clearcell, tanycytic), anaplastic ependymoma), optic nerve glioma, andnon-gliomas (e.g., choroid plexus tumors, neuronal and mixedneuronal-glial tumors, pineal region tumors, embryonal tumors,medulloblastoma, meningeal tumors, primary CNS lymphomas, germ celltumors, pituitary adenomas, cranial and paraspinal nerve tumors, stellarregion tumors), neurofibroma, meningioma, peripheral nerve sheathtumors, peripheral neuroblastic tumours (including without limitationneuroblastoma, ganglioneuroblastoma, ganglioneuroma), trisomy 19ependymoma); neuroendocrine tissues (e.g., paraganglionic systemincluding adrenal medulla (pheochromocytomas) and extra-adrenalparaganglia ((extra-adrenal) paragangliomas); skin (e.g., clear cellhidradenoma, cutaneous benign fibrous histiocytomas, cylindroma,hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma),pilomatricoma, Spitz tumors); and soft tissues (e.g., aggressiveangiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma,angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma,biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcomaprotuberans, desmoid-type fibromatosis, small round cell tumor,desmoplastic small round cell tumor, elastofibroma, embryonalrhabdomyosarcoma, Ewing's tumors/primitive neurectodermal tumors (PNET),extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma,paraspinal sarcoma, inflammatory myofibroblastic tumor, bpoblastoma,lipoma, chondroid lipoma, bposarcoma/malignant lipomatous tumors,bposarcoma, myxoid bposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma,malignant myoepithelioma, malignant melanoma of soft parts,myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblasticsarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, nonrhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissueleiomyosarcoma, undifferentiated sarcoma, well-differentiatedbposarcoma.

In some embodiments, the cancer is a melanoma, a gastric cancer, atriple-negative breast cancer (TNBC), a non-small cell lung cancer(NSCLC), a rectal adenocarcinoma, a colorectal cancer, a renal cellcarcinoma, an ovarian cancer, a prostate cancer, an oral squamous cellcarcinoma (SCC), a head and neck squamous cell carcinoma (HNSCC), aurothelial bladder cancer, a glioblastoma (GBM), a meningioma, adrenalcancer, or an endometrial cancer.

In some embodiments, the method further comprises administering one ormore additional therapeutic agents to the subject. The additionaltherapeutic agent can include any therapeutic agent described above forcombination therapy. In some embodiments, the additional therapeuticagent is independently an anti-neoplastic agent, nivolumab,pembrolizumab, atezolizumab, ipilimumab, chemotherapy, radiationtherapy, or resection therapy. In some embodiments, the additionaltherapeutic agent is independently rituxan, doxorubicin, gemcitabine,nivolumab, pembrolizumab, nivolumab, pembrolizumab, atezolizumab, oripilimumab.

In some embodiments, the additional therapeutic agent is a PD-1/PD-L1inhibitor.

In some embodiments, the anti-neoplastic agent is an anti-microtubuleagent, a platinum coordination complex, an alkylating agent, anantibiotic agent, a topoisomerase II inhibitor, an antimetabolite, atopoisomerase I inhibitor, a hormone or hormonal analogue, a signaltransduction pathway inhibitor, a non-receptor tyrosine kinaseangiogenesi, an inhibitor, an immunotherapeutic agent, a proapoptoticagent, a cell cycle signaling inhibitor, a proteasome inhibitor, ainhibitor of cancer metabolism, an anti-PD-L1 agent, a PD-1 antagonist,an immuno-modulator, a STING modulating compound, a CD39 inhibitor, anA2a and A2a adenosine antagonist, a TLR4 antagonist, an antibody toICOS, or OX40.

In some embodiments, the compound or pharmaceutical composition isco-administered with one or more additional therapeutic agentscomprising an activator or agonist of a fins related tyrosine kinase 3(FLT3; CD135) receptor, a toll-like receptor (TLR) or a stimulator ofinterferon genes (STING) receptor.

In some embodiments, the TLR agonist or activator is a TLR2 agonist, aTLR3 agonist, a TLR7 agonist, a TLR8 agonist and a TLR9 agonist.

In some embodiments, the STING receptor agonist or activator is ADU-S100(MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING,MSA-1, SR-8291, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),cyclic-GAMP (cGAMP) and cyclic-di-AMP.

In some embodiments, the compound or pharmaceutical composition isco-administered with one or more additional therapeutic agentscomprising an inhibitor or antagonist of: protein tyrosine phosphatase,non-receptor type 11 (PTPN11 or SHP2), myeloid cell leukemia sequence 1(MCL1) apoptosis regulator; mitogen-activated protein kinase kinasekinase kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1(HPK1)); diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha);5′-nucleotidase ecto (NTSE or CD73); transforming growth factor beta 1(TGFB1 or TGF); heme oxygenase 1 (HMOX1, HO-1 or H01); vascularendothelial growth factor A (VEGFA or VEGF); erb-b2 receptor tyrosinekinase 2 (ERBB2 HER², HER2/neu or CD340); epidermal growth factorreceptor (EGFR, ERBB, ERBB1 or HER1); ALK receptor tyrosine kinase (ALK,CD246); poly(ADP-ribose) polymerase 1 (PARP1 or PARP); cyclin dependentkinase 4 (CDK4); cyclin dependent kinase 6 (CDK6); C—C motif chemokinereceptor 8 (CCR8, CDw198); CD274 molecule (CD274, PDL1 or PD-L1);programmed cell death 1 (PDCD1, PD1 or PD-1); and/or cytotoxicT-lymphocyte associated protein 4 (CTLA4, CTLA-4, CD152).

In some embodiments, the inhibitor comprises an antigen bindingmolecule, an antibody or an antigen-binding fragment thereof.

In some embodiments, the inhibitor of MCL1 is AMG-176, AMG-397, S-64315,AZD-5991, 483-LM, A1210477, UMI-77, or JKY-5-037.

In some embodiments, the inhibitor of PTPN11 or SHP2 is TN0155(SHP-099), RMC-4550, JAB-3068 and RMC-4630.

In some embodiments, the additional therapeutic agent is achemotherapeutic, an anti-neoplastic, a radiotherapeutic, or acheckpoint targeting agent. In some embodiments, the one or moreanti-neoplastic or chemotherapeutic agents are a nucleoside analog(e.g., 5-fluorouracil, gemcitabine, cytarabine), a taxane (e.g.,paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel), a platinumcoordination complex (cisplatin, carboplatin, oxaliplatin, nedaplatin,triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin,dicycloplatin, eptaplatin, lobaplatin, miriplatin), a dihydrofolatereductase (DHFR) inhibitor (e.g., methotrexate, trimetrexate,pemetrexed), a topoisomerase inhibitor (e.g., doxorubicin, daunorubicin,dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan,mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398(liposomal irinotecan), vosaroxin and GPX-150, al doxorubicin, AR-67,mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114)), analkylating agent (e.g., a nitrogen mustard (e.g., cyclophosphamide,chlormethine, uramustine or uracil mustard, melphalan, chlorambucil,ifosfamide, bendamustine, temozolomide, carmustine), a nitrosourea(e.g., carmustine, lomustine, streptozocin), an alkyl sulfonate (e.g.,busulfan)), or mixtures thereof.

In some embodiments, the checkpoint targeting agent is an antagonistanti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonistanti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonistanti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonistanti-CEACAM1 antibody, an agonist anti-GITR antibody, an antagonistanti-TIGIT antibody, an antagonist anti-VISTA antibody, an agonistanti-CD 137 antibody, or an agonist anti-OX40 antibody.

In some embodiments, the additional therapeutic agent comprises one ormore cellular therapies. In some embodiments, the cellular therapycomprises one or more of a population of natural killer (NK) cells, NK-Tcells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC)cells, tumor infiltrating lymphocytes (TILs) and/or dendritic cells(DCs). In some embodiments, the cellular therapy entails a T celltherapy, e.g., co-administering a population of alpha/beta TCR T cells,gamma/delta TCR T cells, regulatory T (Treg) cells and/or TRuC™ T cells.In some embodiments, the cellular therapy entails a NK cell therapy,e.g., co-administering NK-92 cells. A cellular therapy can entail theco-administration of cells that are autologous, syngeneic or allogeneicto the subject. In some embodiments, the cells are allogeneic to anintended recipient. In some embodiments, the one or more of a populationof immune cells comprise one or more chimeric antigen receptors (CARs).

In some embodiments, the checkpoint targeting agent is an antagonistanti-PD-1 antibody, an antagonist anti-PD-L1 antibody, an antagonistanti-PD-L2 antibody, an antagonist anti-CTLA-4 antibody, an antagonistanti-TIM-3 antibody, an antagonist anti-LAG-3 antibody, an antagonistanti-CEACAM1 antibody, an agonist anti-GITR antibody, an antagonistanti-TIGIT antibody, an antagonist anti-VISTA antibody, an agonistanti-CD 137 antibody, or an agonist anti-OX40 antibody.

VII. Examples Abbreviations

Certain abbreviations and acronyms are used in describing theexperimental details. Although most of these would be understood by oneskilled in the art, Table 1 contains a list of many of theseabbreviations and acronyms.

TABLE 1 List of abbreviations and acronyms. Abbreviation Definition Acacetate Ar argon ACN acetonitrile cat catalyst DCM dichloromethane DIPEAN,N-diisopropylethylamine DMSO dimethylsulfoxide DMF dimethylformamideES/MS electrospray mass spectrometry Et ethyl EtOAc ethyl acetate HPLChigh performance liquid chromatography LC liquid chromatography Memethyl MeCN acetonitrile m/z mass to charge ratio NMPN-methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance Ph phenylPd(dppf)Cl₂ or [1,1′-Bis(diphenylphosphino)ferrocene] PdCl₂(dppf)dichloropalladium(II) Pr propyl RP reverse phase TFA trifluoroaceticacid THF tetrahydrofuran TBHP tert-butyl hydroperoxide δ parts permillion referenced to residual non-deuterated solvent peak

A. Intermediates Suzuki Cross Coupling with Cyclopropyl Boronic AcidsIntermediate 1. 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine

6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine was prepared asfollows: A microwave vial was charged with8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine (200 mg, 0.81 mmol, 1equiv), cyclopropylboronic acid (73.2 mg, 0.85 mmol, 1.05 equiv), cesiumcarbonate (529 mg, 1.62 mmol, 2 equiv), and Pd(dppf)Cl₂CH₂Cl₂ (66.3 mg,10 mol %). The reaction mixture was dissolved in 1:1 dioxane/H₂O (4 mLtotal), purged with argon, and heated in a microwave reactor at 120° C.After 1 hour, the reaction mixture was directly purified by silica gelchromatography (0-10% MeOH/CH₂Cl₂). Fractions obtained were mixtures ofmono and bis-alkylated products. Compound was repurified by silica gelchromatography (0-100% EtOAc/Hexanes), affording6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine. ES/MS m/z:208.10 [M+H].

Intermediate 2. 6-chloro-8-cyclopropyl-2-phenyl-imidazo[1,2-b]pyridazine

6-chloro-8-cyclopropyl-2-phenyl-imidazo[1,2-b]pyridazine was prepared inthe manner described for Intermediate 1, but replacing8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-2-phenylimidazo[1,2-b]pyridazine. ES/MS m/z: 270.10[M+H].

Intermediate 3. Ethyl6-chloro-8-cyclopropyl-imidazo[1,2-b]pyridazine-2-carboxylate

Ethyl 6-chloro-8-cyclopropyl-imidazo[1,2-b]pyridazine-2-carboxylate wasprepared in the manner described for Intermediate 1, but replacing8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with ethyl8-bromo-6-chloro-imidazo[1,2-b]pyridazine-2-carboxylate. ES/MS m/z:266.10 [M+H].

Intermediate 4. 6-chloro-8-cyclopropylimidazo[1,2-b]pyridazine

8-bromo-6-chloroimidazo[1,2-b]pyridazine (103 mg, 0.43 mmol, 1 equiv),cyclopropylboronic acid (81 mg, 0.92 mmol, 2.1 equiv), Pd(dppf)Cl₂-DCMcomplex (9 mg, 0.01 mmol, 0.02 equiv), and Cs₂CO₃ (357 mg, 1.08 mmol,2.5 equiv) were diluted with 1,4-dioxane (1 mL) and water (1 mL). Themixture was purged with Ar and heated in a microwave reactor at 150° C.for 1 h. The reaction mixture was filtered through Celite, diluted withEtOAC (30 mL), washed with water (25 mL) and brine (25 mL), dried overNa₂SO₄, and concentrated in vacuo. Purification of the reaction productby silica gel chromatography (0-100% EtOAc/DCM) afforded6-chloro-8-cyclopropylimidazo[1,2-b]pyridazine. ES/MS: 194.09 [M+1].

Suzuki Cross Coupling with Cyclopropyl Boronate Esters Intermediate 5.6-chloro-8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]-pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]-pyridazine wasprepared as a racemic mixture follows: A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (100 mg, 0.43 mmol, 1 equiv),racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolane(105 mg, 0.43 mmol, 1 equiv), cesium carbonate (280 mg, 0.86 mmol, 2equiv), and Pd(dppf)Cl₂CH₂Cl₂ (32 mg, 10 mol %). The solids weredissolved in 2:1 dioxane/H₂O (2 mL), purged with argon, and heated in amicrowave reactor at 120° C. After 1 hour, the reaction mixture wasdirectly purified by silica gel chromatography (0-10% MeOH/CH₂Cl₂),affording6-chloro-8-((1S,2S)-2-phenylcyclopropyl)-imidazo[1,2-b]pyridazine. ES/MSm/z: 270.10 [M+H].

Intermediate 6.6-chloro-8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-((1S,2S)-2-(methoxymethyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 238.10 [M+H].

Intermediate 7.6-chloro-8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazine was preparedin the manner described for Intermediate 5 modified as follows. Racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolaneand Pd(dppf)Cl₂·CH₂Cl₂ were replaced with potassium spiro[2.3]hexan-1-yltrifluoroborate and cataCXium-A-PdG3, respectively. The reaction mixturewas dissolved in 10:1 Toluene/H₂O, rather than in 2:1 dioxane/H₂O, andheated at 100° C. for 18 hours. ES/MS m/z: 234.10 [M+H].

Intermediate 8.8-((1S,2S)-2-(tert-butyl)cyclopropyl)-6-chloroimidazo[1,2-b]pyridazine

8-((1S,2S)-2-(tert-butyl)cyclopropyl)-6-chloroimidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith racemic2-((1S,2S)-2-(tert-butyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane.ES/MS m/z: 250.10 [M+H].

Intermediate 9.8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-6-chloroimidazo[1,2-b]pyridazine

8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-6-chloroimidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith racemic2-((1S,2S)-[1,1′-bi(cyclopropan)]-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 234.10 [M+H].

SNAr Reaction of Cyclic Amines with8-bromo-6-chloroimidazo[1,2-b]pyridazine Intermediate 10.6-chloro-8-pyrrolidin-1-yl-imidazo[1,2-b]pyridazine

6-chloro-8-pyrrolidin-1-yl-imidazo[1,2-b]pyridazine was prepared asfollows: A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (200 mg, 0.86 mmol, 1 equiv),pyrrolidine (0.086 mL, 1.03 mmol, 1.2 equiv), DIPEA (0.246 mL, 1.38mmol, 1.6 equiv), and MeCN (5 mL). The reaction mixture was heated to85° C. After 24 hours, the reaction mixture was concentrated. Theresidue obtained was triturated with water, the resulting solids werefiltered, washed with water, and dried affording6-chloro-8-pyrrolidin-1-yl-imidazo[1,2-b]pyridazine. ES/MS m/z: 223.10.

Intermediate 11. 4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)morpholine

4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)morpholine was prepared in themanner described for Intermediate 10, but replacing pyrrolidine withmorpholine. ES/MS m/z: 239.10 [M+H].

SNAr Reaction of Benzylamines with8-bromo-6-chloroimidazo-[1,2-b]pyridazine Intermediate 12.N-benzyl-6-chloroimidazo[1,2-b]-pyridazin-8-amine

N-benzyl-6-chloroimidazo[1,2-b]-pyridazin-8-amine was prepared asfollows: To a solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (200mg, 0.860 mmol, 1 equiv) and triethylamine (0.361 mL, 2.58 mmol, 3equiv) in EtOH (1.6 mL) was added benzylamine (0.094 mL, 0.860 mmol, 1equiv). The reaction mixture was heated to 90° C., in a sealed microwavevial, and stirred overnight. The reaction mixture was diluted withEtOAc/water and extracted twice with EtOAc. The combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo to provideN-benzyl-6-chloroimidazo[1,2-b]pyridazin-8-amine. The product was useddirectly in subsequent reaction(s) without further purification. ES/MSm/z: 259.1 [M+1].

Intermediate 13.N-benzyl-6-chloro-N-methylimidazo[1,2-b]pyridazin-8-amine

N-benzyl-6-chloro-N-methylimidazo[1,2-b]pyridazin-8-amine was preparedin the manner described for Intermediate 12, but replacing benzylaminewith N-methyl-1-phenylmethanamine (0.111 mL, 0.860 mmol, 1 equiv). ES/MSm/z: 273.1 [M+1].

Intermediate 14. 6-chloro-8-imidazol-1-yl-imidazo[1,2-b]pyridazine

A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (250 mg, 1.08 mmol, 1 equiv),imidazole (80.5 mg, 1.18 mmol, 1.1 equiv), potassium carbonate (233 mg,1.61 mmol, 1.5 equiv), and NMP (5 mL). The reaction mixture was heatedto 90° C. After 8 hours, the reaction mixture was diluted with water,the resulting solids were filtered, washed with water and dried toprovide 6-chloro-8-imidazol-1-yl-imidazo[1,2-b]pyridazine. ES/MS m/z:220.10 [M+H].

SnAr Reaction of Alcohols with 8-Bromo-6-chloroimidazo-[1,2-b]pyridazineIntermediate 15. 6-chloro-8-cyclopropoxyimidazo[1,2-b]pyridazine

8-bromo-6-chloroimidazo[1,2-b]pyridazine (528 mg, 2.27 mmol) andcyclopropanol (119 mg, 2.04 mmol) were dissolved in ACN (5 mL). To thereaction mixture was added cesium carbonate (1.1 g, 3.41 mmol) andheated at 80° C. overnight. The reaction mixture was then concentratedin vacuo and purified by silica gel chromatography to afford6-chloro-8-cyclopropoxyimidazo-[1,2-b]pyridazine. ES/MS m/z: 210.10[M+H].

Intermediate 16.5-(8-isopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-isopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows. A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (300 mg, 1.29 mmol, 1 equiv),2-propanol (0.296 mL, 3.87 mmol, 3 equiv), cesium carbonate (841 mg,2.58 mmol, 2 equiv), and MeCN (5 mL). The reaction mixture was heated to80° C. After 24 hours, the reaction mixture was directly purified bysilica gel chromatography (0-100% EtOAc/Hexanes), affording6-chloro-8-isopropoxyimidazo[1,2-b]pyridazine. ES/MS m/z: 212.00.

Intermediate 17. 8-benzyloxy-6-chloro-imidazo[1,2-b]pyridazine

8-benzyloxy-6-chloro-imidazo[1,2-b]pyridazine was prepared as follows.To a solution of phenylmethanol (47 uL, 0.452 mmol) in THF (1.5 mL) at0° C. was added sodium hydride (18 mg, 0.473 mmol). The reaction mixturewas stirred for 30 min, after which8-bromo-6-chloro-imidazo[1,2-b]pyridazine (100 mg, 0.430 mmol) as addedas a solution in THF (0.5 mL). The mixture was stirred overnight andslowly warmed to room temperature. The mixture was then quenched withH₂O and extracted with EtOAc. Combined organics were dried over MgSO₄,filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (0-100% EtOAc/hexanes) to provide the titlecompound. ES/MS m/z: 260.1 [M+1].

Suzuki Cross Coupling Reaction with (2,4-dimethoxypyrimidin-5-yl)boronicAcid Intermediate 18.8-cyclopropyl-6-(2,4-dimethoxy-pyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazine

8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewas prepared as follows: A microwave vial was charged with(2,4-dimethoxypyrimidin-5-yl)boronic acid (59.4 mg, 0.323 mmol, 1.0equiv), Pd(dppf)Cl₂—CH₂Cl₂ (23.6 mg, 0.032 mmol, 10 mol %), Cs₂CO₃ (210mg, 0.645 mmol, 2 equiv) and6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine (67 mg, 0.323mmol, 1 equiv). The reaction mixture was dissolved in 3:1 dioxane/H₂O (4mL), purged with argon, and was stirred at 80° C. for 5 h. The reactionmixture was directly purified by silica gel chromatography (0-15%MeOH/CH₂Cl₂). Compound was repurified by SiO₂ chromatography (0-100%EtOAc/Hexanes), affording8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazine.ES/MS m/z: 312.20 [M+H].

Intermediate 19.8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-phenyl-imidazo[1,2-b]pyridazine

8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-phenyl-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-cyclopropyl-2-phenyl-imidazo[1,2-b]pyridazine. ES/MS m/z:374.20 [M+H].

Intermediate 20. Ethyl8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylate

Ethyl8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylatewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with ethyl6-chloro-8-cyclopropyl-imidazo[1,2-b]pyridazine-2-carboxylate. ES/MSm/z: 370.10 [M+H].

Intermediate 21.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 342.10 [M+H].

Intermediate 22.6-(2,4-dimethoxypyrimidin-5-yl)-8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazine (racemicmixture). ES/MS m/z: 338.20 [M+H].

Intermediate 23.8-((1S,2S)-2-(tert-butyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(tert-butyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with8-((1S,2S)-2-(tert-butyl)cyclopropyl)-6-chloroimidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 354.10 [M+H].

Intermediate 24.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 374.20 [M+H].

Intermediate 25.8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine wasprepared as a racemic mixture in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-6-chloroimidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 338.20 [M+H].

Intermediate 26.6-(2,4-dimethoxypyrimidin-5-yl)-8-pyrrolidin-1-yl-imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-pyrrolidin-1-yl-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-pyrrolidin-1-yl-imidazo[1,2-b]pyridazine. ES/MS m/z: 327.20[M+H].

Intermediate 27.4-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]morpholine

4-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]morpholinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)morpholine. ES/MS m/z: 343.20[M+H].

Intermediate 28.6-(2,4-dimethoxypyrimidin-5-yl)-8-imidazol-1-yl-imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-imidazol-1-yl-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-imidazol-1-yl-imidazo[1,2-b]pyridazine. ES/MS m/z: 324.10[M+H].

Intermediate 29.N-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-amine

N-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-aminewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine withN-benzyl-6-chloroimidazo[1,2-b]pyridazin-8-amine (60 mg, 0.232 mmol, 1equiv). ES/MS m/z: 363.2 [M+1].

Intermediate 30.N-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)-N-methylimidazo[1,2-b]pyridazin-8-amine

N-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)-N-methylimidazo[1,2-b]pyridazin-8-aminewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine withN-benzyl-6-chloro-N-methylimidazo[1,2-b]pyridazin-8-amine (90 mg, 0.330mmol, 1 equiv). ES/MS m/z: 377.2 [M+1].

Intermediate 31. 6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

6-bromoimidazo[1,2-b]pyridazine (200 mg, lmmol) and(2,4-dimethoxypyrimidin-5-yl)boronic acid (252 mg, 1.62 mmol) weredissolved in dioxane/water (2/1, 4 mL). To the reaction mixture wasadded cesium carbonate (823 mg, 2.52 mmol) and Pd(dppf)Cl₂ (82 mg, 0.1mmol). The reaction mixture was then purged with Argon for 10 mins andthen heated at 110° C. overnight. The reaction mixture was then filteredand purified with reverse phase HPLC (ACN/water with 0.1% TFA) to afford6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine. ES/MS m/z:230.10 [M+H].

Intermediate 32.8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

6-chloro-8-cyclopropylimidazo[1,2-b]pyridazine (37 mg, 0.19 mmol, 1equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (37 mg, 0.19 mmol, 1equiv), Pd(dppf)Cl₂ DCM complex (15 mg, 0.02 mmol, 0.1 equiv), andCs₂CO₃ (157 mg, 0.48 mmol, 2.5 equiv) were diluted with 1,4-dioxane (1.0mL) and water (0.5 mL). The mixture was purged with Ar and set into amicrowave reactor to 120° C. for 1 h. The mixture was filtered throughcelite, diluted with EtOAC (30 mL), washed with water (30 mL) and brine(30 mL), dried over Na₂SO₄, and concentrated in vacuo. Purification bycolumn chromatography (0-30% MeOH/DCM) afforded8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS: 298.15 [M+1].

Intermediate 33.8-cyclopropoxy-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

6-chloro-8-cyclopropoxyimidazo[1,2-b]pyridazine (131 mg, 0.625 mmol) and(2,4-dimethoxypyrimidin-5-yl)boronic acid (230 mg, 1.25 mmol) weredissolved in dioxane/water (2/1, 4 mL). To the reaction mixture wasadded cesium carbonate (509 mg, 1.56 mmol) and Pd(dppf)Cl₂ (46 mg, 0.06mmol). The reaction mixture was then purged with argon for 10 mins andthen heated at 110° C. overnight. The reaction mixture was then filteredand purified with a combi-flash column to afford8-cyclopropoxy-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]. ES/MS m/z:314.20 [M+H].

Intermediate 34.5-(8-isopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-isopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows. A microwave vial was charged with6-chloro-8-isopropoxyimidazo[1,2-b]pyridazine (91 mg, 0.43 mmol, 1equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (119 mg, mmol, 1.5equiv), cesium carbonate (280 mg, 0.86 mmol, 2 equiv), andPd(dppf)Cl₂·CH₂Cl₂ (32 mg, 10 mol %). The reaction mixture was dissolvedin 2:1 dioxane/H₂O (4 mL), purged with argon, and heated at 80° C. After30 minutes, the reaction mixture was directly purified by SiO₂chromatography (0-30% EtOAc/CH₂Cl₂), affording6-(2,4-dimethoxypyrimidin-5-yl)-8-isopropoxyimidazo[1,2-b]pyridazine.ES/MS m/z: 316.20 [M+H].

Intermediate 35.8-benzyloxy-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-benzyloxy-6-chloro-imidazo[1,2-b]pyridazine (54 mg, 0.208 mmol),(2,4-dimethoxypyrimidin-5-yl) boronic acid (46 mg, 0.250 mmol),Pd(dppf)Cl₂—CH₂Cl₂ (17 mg, mmol), and Cs₂CO₃ (203 mg, 0.624 mmol) werecombined in a microwave vial. Dioxane (1 mL) and H₂O (0.2 mL) were thenadded and the mixture was degassed with N₂ for 5 min. The vial was thensealed and heated to 90° C. overnight. The mixture was concentrated invacuo and purified by silica gel chromatography (0-100% EtOAc/hexanes)to provide the title compound. ES/MS m/z: 364.1 [M+1].

Two-Step C—H Alkylation and Suzuki Sequence with6-Chloroimidazo[1,2-b]pyridazine Intermediate 36.8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as follows:

Preparation of6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine

To a solution of 6-chloroimidazo[1,2-b]pyridazine (75 mg, 0.488 mmol, 1equiv) and sodium 4,4-difluorocyclohexane sulfinate (252 mg, 1.22 mmol,2.5 equiv) in DMSO/water (5:1, 1.5 mL total) was addedtert-butylhydroperoxide (0.349 mL-70% in H₂O, 2.44 mmol, 5 equiv). Thereaction mixture was heated to 50° C. and stirred overnight.Subsequently, the reaction mixture was diluted with EtOAc/water andextracted twice with EtOAc. The combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo. The resulting product wasused directly in the next step without further purification. ES/MS m/z:272.1 [M+1].

Preparation of8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

A freshly degassed solution of the resulting product from the reactionabove, 6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine (133mg, 0.504 mmol, 1 equiv), in dioxane/water (5:1, 3 mL total) was addedto the solid reagents (2,4-dimethoxypyrimidin-5-yl)boronic acid (111 mg,0.605 mmol, 1.2 equiv), Pd(dppf)Cl₂—CH₂Cl₂ (41 mg, 0.050 mmol, 10 mol%), and Cs₂CO₃ (493 mg, 1.51 mmol, 3 equiv) under an atmosphere ofnitrogen. The reaction mixture was heated to 90° C. and stirredovernight. The reaction mixture was diluted with EtOAc/water andextracted twice with EtOAc. The combined organic layers were dried overMgSO₄, filtered, and concentrated in vacuo. The resulting product waspurified by silica gel chromatography (0-100% EtOAc/hexanes) to provide8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 376.2 [M+1].

Intermediate 37.6-chloro-8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine

6-chloro-8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 36 with the followingmodifications. 6-chloroimidazo[1,2-b]pyridazine, of the Intermediate 36procedure, was replaced with6-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridine (100 mg, 0.451 mmol,1 equiv) and sodium 4,4-difluorocyclohexane sulfinate was replaced withzinc diisopropyl sulfinate (252 mg, 0.903 mmol, 2 equiv). ES/MS m/z:264.1 [M+1].

Intermediate 38.6-(2,4-dimethoxypyrimidin-5-yl)-8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 36, but using6-chloro-8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine (89 mg,0.338 mmol, 1 equiv) in place of6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine. ES/MS m/z:368.1 [M+1].

Intermediate 39. 6-chloro-8-isopropyl-[1,2,4]triazolo[4,3-a]pyridazine

6-chloro-8-isopropyl-[1,2,4]triazolo[4,3-a]pyridazine was prepared inthe manner described for Intermediate 36, but using6-chloro-[1,2,4]triazolo[4,3-b]pyridazine (75 mg, 0.485 mmol, 1 equiv)in place of 6-chloroimidazo[1,2-b]pyridazine and zinc diisopropylsulfinate (271 mg, 0.971 mmol, 2 equiv) in place of sodium4,4-difluorocyclohexane sulfinate. ES/MS m/z: 197.1 [M+1].

Intermediate 40.6-(2,4-dimethoxypyrimidin-5-yl)-8-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-isopropyl-[1,2,4]triazolo[4,3-b]pyridazinewas prepared in the manner described for Intermediate 36, but using6-chloro-8-isopropyl-[1,2,4]triazolo[4,3-a]pyridazine (83 mg, 0.422mmol, 1 equiv) in place of6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine. ES/MS m/z:301.2 [M+1].

Intermediate 41. 8-benzyl-6-chloro-imidazo[1,2-b]pyridazine

8-benzyl-6-chloro-imidazo[1,2-b]pyridazine was prepared in the mannerdescribed for Intermediate 36, but using zinc benzylsulfinate (367 mg,0.977 mmol, 2 equiv) in place of sodium 4,4-difluorocyclohexanesulfinate. ES/MS m/z: 244.1 [M+1].

Intermediate 42.8-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 36, but using8-benzyl-6-chloro-imidazo[1,2-b]pyridazine (37 mg, 0.152 mmol) in placeof 6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine. ES/MSm/z: 348.2 [M+1].

Intermediates 43 and 44.6-chloro-8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine and6-chloro-2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine(Intermediate 43) and6-chloro-2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine(Intermediate 44) were prepared in the manner described for Intermediate36, but using sodium 1-(trifluoromethyl)cyclopropanesulfinate (239 mg,1.22 mmol, 2.5 equiv) in place of sodium 4,4-difluorocyclohexanesulfinate. The two products were isolated separately using via silicagel chromatography.

Intermediate 43:6-chloro-8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazineES/MS m/z: 262.1 [M+1].

Intermediate 44:6-chloro-2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazineES/MS m/z: 370.1 [M+1]

Intermediate 45.6-(2,4-dimethoxypyrimidin-5-yl)-8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 36, but using6-chloro-8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine (12mg, 0.046 mmol, 1 equiv) in place of6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine. ES/MS m/z:366.1 [M+1].

Intermediate 46.6-(2,4-dimethoxypyrimidin-5-yl)-2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 36, but6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine with6-chloro-2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine(23 mg, 0.062 mmol, 1 equiv). ES/MS m/z: 474.1 [M+1].

Intermediates 47 and 48.8-(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine and2,8-bis(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine

8-(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine(Intermediate 47) and2,8-bis(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine(Intermediate 48) were prepared in the manner described for Intermediate36, but using zinc bis[(phenylsulfonyl)methanesulfinate] (492 mg, 0.977mmol, 2 equiv) in place of sodium 4,4-difluorocyclohexane sulfinate. Thetwo products were isolated separately using via silica gelchromatography.

Intermediate 47:8-(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine ES/MS m/z:308.0 [M+1].

Intermediate 48:2,8-bis(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine ES/MSm/z: 462.0 [M+1]

Intermediate 49.8-(benzenesulfonylmethyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(benzenesulfonylmethyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 36, but replacing6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine with8-(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine (30 mg,0.098 mmol, 1 equiv). ES/MS m/z: 412.1 [M+1].

Intermediate 50.2,8-bis(benzenesulfonylmethyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

2,8-bis(benzenesulfonylmethyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 36, but replacing6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine with2,8-bis(benzenesulfonylmethyl)-6-chloro-imidazo[1,2-b]pyridazine (13 mg,0.028 mmol, 1 equiv). ES/MS m/z: 566.1 [M+1].

C—H Alkylation Reactions Intermediate 51.6-chloro-8-(4,4-difluorocyclohexyl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine

To a mixture of 6-chloro-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine (75mg, 0.445 mmol) and sodium 4,4-difluorocyclohexanesulfinate (229 mg,1.11 mmol) in DMSO (1.26 mL) and water (0.252 mL) was added tert-butylhydroperoxide solution (70% in water, 0.318 mL, 2.22 mmol). The mixturewas heated to 50° C. and stirred for 2 h. The mixture was then dilutedwith water and extracted with EtOAc. The combined organics were driedover MgSO₄, filtered, and concentrated in vacuo. The resulting residuewas purified by silica gel chromatography (0-100% EtOAc/hexanes) toafford6-chloro-8-(4,4-difluorocyclohexyl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 287.1 [M+1].

Intermediate 52.6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine-3-carbonitrile

6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine-3-carbonitrilewas prepared in the manner described for Intermediate 51, but replacing6-chloro-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine with6-chloroimidazo[1,2-b]pyridazine-3-carbonitrile. ES/MS m/z: 297.1 [M+1].

Intermediate 53.6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-imidazo[1,2-b]pyridazine

6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 51, but replacing6-chloro-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine with6-chloro-3-methyl-imidazo[1,2-b]pyridazine. ES/MS m/z: 286.1 [M+1].

Intermediate 54. 8-((benzyloxy)methyl)-6-chloroimidazo[1,2-b]pyridazine

To the solids 6-chloroimidazo[1,2-b]pyridazine (0.150 g, 0.977 mmol, 1equiv), ((benzyloxy)methyl)trifluoroborane potassium salt (0.178 g, 1.47mmol, 1.5 equiv), K2S208 (0.528 g, 1.95 mmol, 2 equiv) and9-Mesityl-10-methylacridinium tetrafluoroborate (0.0195 g, mmol, 5 mol%) was added acetonitrile (4.8 mL), water (4.8 mL) and TFA (0.075 mL,mmol, 1 equiv). The reaction mixture was stirred in a fan cooled, BlueLED photoreactor for 16 hours. The reaction was quenched with saturatedaqueous NaHCO₃, extracted twice with EtOAc, the combined organic layerswere dried over MgSO₄, filtered and concentrated in vacuo. The productwas purified by silica gel chromatography to provide8-((benzyloxy)methyl)-6-chloroimidazo[1,2-b]pyridazine. ES/MS m/z:274.05 [M+H].

SNAr Reaction with Cyclic Amines Intermediate 55.6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine

To a mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (150 mg, 0.645mmol) and 3-phenylazetidine hydrochloride (109 mg, 0.645 mmol) in MeCN(2 mL) was added N,N-diisopropylethylamine (0.337 mL, 1.94 mmol). Themixture was heated to 100° C. and stirred for 4 h. The mixture was thenconcentrated in vacuo and the resulting residue was purified by silicagel chromatography (0-100% EtOAc/hexanes) to afford6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MS m/z:285.1 [M+1].

Intermediate 56.6-chloro-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 55, but replacing3-phenylazetidine hydrochloride with 3-(trifluoromethyl)azetidine. ES/MSm/z: 277.1 [M+1].

Intermediate 57.6-chloro-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 55, but replacing3-phenylazetidine hydrochloride with 3,3-dimethylazetidinehydrochloride. ES/MS m/z: 237.1 [M+1].

Intermediate 58.6-chloro-8-(2-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine (RacemicMixture)

6-chloro-8-(2-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine was preparedas a racemic mixture in the manner described for Intermediate 55, butreplacing 3-phenylazetidine hydrochloride with 2-phenylazetidine. ES/MSm/z: 285.1 [M+1].

Intermediate 59.6-chloro-8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine

A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (250 mg, 1.08 mmol, 1 equiv),3,3-dimethylpyrrolidine hydrochloride (160 mg, 1.18 mmol, 1.1 equiv),DIPEA (0.481 mL, 2.69 mmol, 2.5 equiv), and MeCN (5 mL). The reactionmixture was heated to 85° C. After 24 hours, the reaction mixture wasconcentrated. The residue obtained was triturated with water, theresulting solids were filtered, washed with water, and dried affording6-chloro-8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 251.10 [M+1].

Intermediate 60.6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 59, but replacing3,3-dimethylpyrrolidine hydrochloride with3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride. ES/MS m/z: 287.10[M+H].

Intermediate 61.6-chloro-8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazine(cis)was prepared in the manner described for Intermediate 59, but replacing3,3-dimethylpyrrolidine hydrochloride with(3S,4R)-3,4-difluoropyrrolidine hydrochloride(cis). ES/MS m/z: 259.10[M+H].

Intermediate 62.6-chloro-8-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazine(transrelative) was prepared in the manner described for Intermediate 59, butreplacing 3,3-dimethylpyrrolidine hydrochloride with(3S,4S)-3,4-difluoropyrrolidine hydrochloride. ES/MS m/z: 259.10 [M+H].

Intermediate 63.6-chloro-8-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 59, but replacing3,3-dimethylpyrrolidine hydrochloride with 3,3-difluoropyrrolidine.ES/MS m/z: 259.10 [M+H].

Intermediate 64.6-chloro-8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazine

6-chloro-8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 59, but replacing3,3-dimethylpyrrolidine hydrochloride with 4,4-dimethylpiperidinehydrochloride. ES/MS m/z: 265.20 [M+H].

Intermediate 65.5-chloro-7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

To a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (0.200 g, 1.06mmol, 1 equiv) in ethanol (1.6 mL) was added K₂CO₃ (0.296 g, 2.13 mmol,2 equiv) and 3,3-dimethylpyrrolidine (0.116 g, 1.17 mmol, 1.1 equiv).The reaction mixture was stirred overnight at 90° C. before beingdiluted with EtOAc, filtered and concentrated in vacuo. The resulting5-chloro-7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine wasused without further purification. ES/MS m/z: 251.08 [M+H].

Intermediate 66.5-chloro-7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 65, but replacing5,7-dichloropyrazolo[1,5-a]pyrimidine with5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine. ES/MS m/z: 252.10 [M+H].

Intermediate 67.6-chloro-8-(3,3-difluoropiperidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoropiperidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 65, but replacing5,7-dichloropyrazolo[1,5-a]pyrimidine with8-bromo-6-chloroimidazo[1,2-b]pyridazine, and 3,3-dimethylpyrrolidinewith 3,3-difluoropiperidine hydrochloride. ES/MS m/z: 273.10 [M+H].

Intermediate 68.8-(3-azabicyclo[3.2.1]octan-3-yl)-6-chloroimidazo[1,2-b]pyridazine

8-(3-azabicyclo[3.2.1]octan-3-yl)-6-chloroimidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 65, but replacing5,7-dichloropyrazolo[1,5-a]pyrimidine with8-bromo-6-chloroimidazo[1,2-b]pyridazine, and 3,3-dimethylpyrrolidinewith 3-azabicyclo[3.2.1]octane. ES/MS m/z: 263.00 [M+H].

Intermediate 69.6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine

To a mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (0.2 g, 0.86mmol) and potassium carbonate (0.24 g, 1.72 mmol) in EtOH (2 mL) wasadded 3,3,4,4-tetrafluoropyrrolidine; hydrochloride (154 mg, 0.86 mmol).The reaction mixture was heated at 90° C. overnight. The solvent wasthen evaporated and the residue was purified by Prep HPLC (10-90%ACN/water with TFA) to afford6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 392.20 [M+H].

Intermediate 70. 6-chloro-8-pyrazol-1-yl-imidazo[1,2-b]pyridazine

A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (250 mg, 1.08 mmol, 1 equiv),1H-pyrazole (80.5 mg, 1.18 mmol, 1.1 equiv), potassium carbonate (233mg, 1.61 mmol, 1.5 equiv), and NMP (5 mL). The reaction mixture washeated to 90° C. After 8 hours, the reaction mixture was diluted withwater, the resulting solids were filtered, washed with water and driedto provide 6-chloro-8-pyrazol-1-yl-imidazo[1,2-b]pyridazine. ES/MS m/z:220.10 [M+H].

Intermediate 71.2-(2-fluoro-2-phenylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: To a solution of 2-fluoro-2-phenyl-cyclopropanecarboxylic acid(500 mg, 2.78 mmol, 1 equiv) in CH₂Cl₂ (10 mL) was addeddiisopropylmethanediimine (0.48 mL, 3.05 mmol, 1.1 equiv),N,N-dimethylpyridin-4-amine (34 mg, 10 mol %), and2-hydroxyisoindoline-1,3-dione (498 mg, 3.05 mmol, 1.1 equiv). After 6hours, the reaction mixture was filtered over celite with CH₂Cl₂washings and concentrated. The residue was purified by SiO₂chromatography (0-100% EtOAc/Hex), affording 1,3-dioxoisoindolin-2-yl2-fluoro-2-phenylcyclopropane-1-carboxylate (mixture of cis and transdiastereomers). ¹H NMR of diastereomeric mixture (400 MHz, Chloroform-d)δ 7.94-7.33 (m), 2.99-2.84 (m, 1H), 2.58-2.36 (m, 2H), 2.22-2.06 (m,2H), 2.01-1.90 (m, 1H).

Step 2: To a solution of 1,3-dioxoisoindolin-2-yl2-fluoro-2-phenylcyclopropane-1-carboxylate (1.00 g, 3.07 mmol, 1 equiv)in EtOAc (15 mL, 0.2M) was added B2Pin2 (1.56 g, 6.15 mmol, 2 equiv) andmethyl isonicotinate (0.18 mL, 1.54 mmol, 0.5 equiv). The resultingmixture was heated to 80° C. under an atmosphere of argon. After 20hours, the reaction mixture was filtered, concentrated, and purified bySiO₂ chromatography (0-50% EtOAc/Hex), affording2-(2-fluoro-2-phenylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Preparation of Chiral Cyclopropyl Boronate Esters Intermediate 72.2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

Step 1: A solution of 5-bromo-2-chlorobenzonitrile (1000 mg, 4.62 mmol,1 equiv), potassium vinyltrifluoroborate (681 mg, 5.08 mmol, 1.1 equiv),and potassium carbonate (1.92 g, 13.9 mmol, 3 equiv) in 9:1 THF/H₂O (10mL) was degassed with Argon. Then, PdCl₂(dppf)-CH₂Cl₂ (169 mg, 5 mol %)was added, and the reaction mixture was heated to 85° C. After 18 hours,the reaction mixture was cooled to room temperature, diluted with H₂O (5mL), and extracted with CH₂Cl₂ (3×20 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated. Purification wasaccomplished by SiO₂ chromatography (0-20% EtOAc/Hex), affording2-chloro-5-vinylbenzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ 7.67 (d,J=2.2 Hz, 1H), 7.60-7.43 (m, 2H), 6.65 (dd, J=17.6, 10.9 Hz, 1H), 5.80(d, J=17.6 Hz, 1H), 5.42 (d, J=10.9 Hz, 1H).

Step 2: To a cooled (0° C.) solution of 2-chloro-5-vinylbenzonitrile(600 mg, 3.67 mmol, 1 equiv) andtetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2-oxazolyl-N]phenyl]ruthenium(II)hexafluorophosphate (23.2 mg, 1 mol %; also known as Ru(II)-(R)-Pheoxcatalyst) in CH₂Cl₂ (37 mL, 0.1M) was added a solution of1,3-dioxoisoindolin-2-yl 2-diazoacetate (1.02 g, 4.40 mmol, 1.2 equiv)in CH₂Cl₂ (15 mL) over 40 minutes. After an additional 4 hours at 0° C.,the reaction mixture was quenched with MeOH (5 mL), concentrated to −10mL, and directly purified by SiO₂ chromatography (0-70% EtOAc/Hex),affording 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-chloro-3-cyanophenyl)cyclopropane-1-carboxylate. Theenantiomeric excess was determined by chiral SFC analysis. ¹H NMR (400MHz, Chloroform-d) δ 7.94-7.87 (m, 2H), 7.84-7.78 (m, 2H), 7.52-7.45 (m,2H), 7.36 (dd, J=8.4, 2.3 Hz, 1H), 2.82-2.74 (m, 1H), 2.27-2.18 (m, 1H),1.94-1.85 (m, 1H), 1.65-1.58 (m, 1H).

Step 3: To a solution of 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-chloro-3-cyanophenyl)cyclopropane-1-carboxylate (1.35 g,3.68 mmol, 1 equiv) and bis(pinacolato)diboron (1.87 g, 7.36 mmol, 2equiv) in EtOAc (74 mL) was added methyl isonicotinate (0.22 mL, 1.84mmol, 0.5 equiv). The reaction mixture was heated to 80° C. After 16hours, the reaction mixture was filtered and concentrated. Purificationwas accomplished by SiO₂ chromatography (0-20% EtOAc/Hex), affording2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.¹H NMR (400 MHz, Chloroform-d) δ 7.38-7.32 (m, 2H), 7.19 (dd, J=8.5, 2.3Hz, 1H), 2.11-2.05 (m, 1H), 1.26-1.23 (m, 13H), 1.03-0.96 (m, 1H),0.32-0.23 (m, 1H).

Intermediate 73.4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 72, but replacing2-chloro-5-vinylbenzonitrile with 4-vinylbenzonitrile. ¹H NMR (400 MHz,Chloroform-d) δ 7.54-7.48 (m, 2H), 7.16-7.10 (m, 2H), 2.12 (dt, J=8.1,5.3 Hz, 1H), 1.29-1.24 (m, 13H), 1.05 (ddd, J=9.9, 5.2, 3.9 Hz, 1H),0.36 (ddd, J=10.0, 7.1, 5.5 Hz, 1H).

Intermediate 74.3-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

3-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 4-bromo-3-fluorobenzonitrile. ¹H NMR(400 MHz, DMSO-d₆) δ 7.76 (dd, J=10.3, 1.7 Hz, 1H), 7.58 (dd, J=8.0, 1.6Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 2.18 (dt, J=8.1, 5.4 Hz, 1H), 1.29-1.21(m, 1H), 1.17 (s, 12H), 0.86-0.79 (m, 1H), 0.34 (ddd, J=9.9, 7.0, 5.6Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −119.16 (dd, J=10.3, 7.7 Hz).

Intermediate 75.4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolane

4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolanewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 1-bromo-4-(trifluoromethyl)benzene. ¹HNMR (400 MHz, Chloroform-d) δ 7.50 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz,2H), 2.20-2.11 (m, 1H), 1.31-1.20 (m, 13H), 1.11-1.02 (m, 1H), 0.41-0.31(m, 1H).

Intermediate 76.4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane

4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolanewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 1-bromo-4-(trifluoromethoxy)benzene.¹H NMR (400 MHz, Chloroform-d) δ 7.10 (s, 4H), 2.16-2.09 (m, 1H), 1.28(s, 6H), 1.27 (s, 6H), 1.23-1.16 (m, 1H), 1.03-0.96 (m, 1H), 0.34-0.26(m, 1H).

Intermediate 77.2-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 4-bromo-2-fluoro-benzonitrile. ¹H NMR(400 MHz, Chloroform-d) δ 7.46 (dd, J=8.1, 6.7 Hz, 1H), 6.93 (dd, J=8.1,1.6 Hz, 1H), 6.86 (dd, J=10.4, 1.6 Hz, 1H), 2.15-2.06 (m, 1H), 1.34-1.18(m, 13H), 1.09-1.00 (m, 1H), 0.42-0.31 (m, 1H).

Intermediate 78.2,3-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2,3-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 4-bromo-2,3-difluoro-benzonitrile. ¹HNMR (400 MHz, Chloroform-d) δ 7.27-7.19 (m, 1H), 6.74-6.63 (m, 1H),2.40-2.30 (m, 1H), 1.37-1.19 (m, 13H), 1.14-1.08 (m, 1H), 0.44-0.34 (m,1H).

Intermediate 79.2-methoxy-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-methoxy-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 4-bromo-2-methoxy-benzonitrile. ¹H NMR(400 MHz, Chloroform-d) δ 7.43 (d, J=8.3 Hz, 1H), 6.71-6.64 (m, 2H),3.92 (s, 3H), 2.18-2.09 (m, 1H), 1.32-1.19 (m, 13H), 1.11-1.01 (m, 1H),0.44-0.35 (m, 1H).

Intermediate 80.2-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 4-bromo-2-methyl-benzonitrile. ¹H NMR(400 MHz, Chloroform-d) δ 7.47 (d, J=8.1 Hz, 1H), 7.02 (s, 1H),6.97-6.90 (m, 1H), 2.51 (s, 3H), 2.13-2.07 (m, 1H), 1.28-1.25 (m, 13H),1.10-1.02 (m, 1H), 0.40-0.31 (m, 1H).

Suzuki Cross Coupling with Cyclopropyl Boronate Esters Intermediate 81.6-chloro-8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture as follows: A microwave vial wascharged with 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (299 mg, 1.29mmol, 1.2 equiv), racemic2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(300 mg, 1.07 mmol, 1 equiv), cesium carbonate (698 mg, 2.14 mmol, 2equiv), and Pd(dppf)Cl₂CH₂Cl₂ (88 mg, 10 mol %). The solids weredissolved in dioxane (3 mL) and H₂O (1.5 mL), and the mixture wasdegassed with N2. The vial was sealed and heated to 120° C. for 4 h. Thereaction mixture was then cooled and filtered through celite, washingwith EtOAc. The filtrate was concentrated in vacuo, and the resultingresidue purified by silica gel chromatography (0-100% EtOAc/hexanes),affording6-chloro-8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 306.0 [M+H].

Intermediate 82.6-chloro-8-[(1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-[(1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 81, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith4,4,5,5-tetramethyl-2-[(1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl]-1,3,2-dioxaborolane.ES/MS m/z: 324.0 [M+1].

Intermediate 83.4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile(Racemic Mixture)

4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 81, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-fluoro-4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile.ES/MS m/z: 313.1 [M+1].

Intermediate 84.5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile(Racemic Mixture)

5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 81, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-fluoro-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile.ES/MS m/z: 313.1 [M+1].

Intermediate 85.6-chloro-8-[(1S,2S)-2-(2,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-[(1S,2S)-2-(2,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 81, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-[(1S,2S)-2-(2,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 306.1 [M+1].

Intermediate 86.6-chloro-8-((1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture as follows: A microwave vial wascharged with 8-bromo-6-chloroimidazo[1,2-b]pyridazine (200 mg, 0.86mmol, 1 equiv), racemic2-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(211 mg, 0.86 mmol, 1 equiv), cesium carbonate (561 mg, 1.72 mmol, 2equiv), and Pd(dppf)Cl₂·CH₂Cl₂ (70.3 mg, 10 mol %). The solids weredissolved in 3:1 dioxane/H₂O (4 mL), purged with argon, and heated at115° C. After 14 hour, the reaction mixture was then filtered andpurified with reverse phase HPLC (ACN/water with 0.1% TFA) to afford6-chloro-8-((1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 271.10 [M+H].

Intermediate 87.6-chloro-8-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture as follows: A microwave vial wascharged with 8-bromo-6-chloroimidazo[1,2-b]pyridazine (150 mg, 0.645mmol, 1 equiv), racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolane(201 mg, 0.645 mmol, 1 equiv), cesium carbonate (420 mg, 1.29 mmol, 2equiv), and Pd(dppf)Cl₂·CH₂Cl₂ (53 mg, 10 mol %). The solids weredissolved in 3:1 dioxane/H₂O (4 mL), purged with argon, and heated in amicrowave reactor at 110° C. After 1.5 hour, the reaction mixture wasdirectly purified by silica gel chromatography (0-15% MeOH/CH₂Cl₂),affording6-chloro-8-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 338.00 [M+H].

Intermediate 88.3-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-5-fluoro-benzonitrile(Racemic Mixture)

3-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-5-fluoro-benzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic3-fluoro-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile.ES/MS m/z: 313.10 [M+H].

Intermediate 89.6-chloro-8-((1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolane.ES/MS m/z: 338.10 [M+H].

Intermediate 90.6-chloro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic3-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine.ES/MS m/z: 271.10 [M+H].

Intermediate 91.6-chloro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine.ES/MS m/z: 271.10 [M+H].

Intermediate 92.6-chloro-3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic2-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 306.10[M+H].

Intermediate 93.6-chloro-3-fluoro-8-[(1S,2S)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-3-fluoro-8-[(1S,2S)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic4,4,5,5-tetramethyl-2-[(1S,2S)-2-phenylcyclopropyl]-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 288.00[M+H].

Intermediate 94.6-chloro-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 87, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith2-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 324.10[M+H].

Intermediate 95.6-chloro-8-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 87, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith2-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 324.10[M+H].

Intermediate 96.6-chloro-8-((1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-(1-naphthyl)cyclopropyl]-1,3,2-dioxaborolane.ES/MS m/z: 320.10 [M+H].

Intermediate 97.6-chloro-2-cyclopropyl-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-2-cyclopropyl-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 87, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolanewith racemic2-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazine. ES/MS m/z:328.10 [M+H].

Intermediate 98.6-chloro-8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith racemic2-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 356.01 [M+H].

Intermediate 99.6-chloro-8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith racemic2-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 322.02 [M+H].

Intermediate 100.6-chloro-8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith racemic2-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 322.03 [M+H].

Intermediate 101.6-chloro-8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith racemic2-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 356.00 [M+H].

Intermediate 102.6-chloro-8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith racemic2-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 300.10 [M+1].

Intermediate 103.6-chloro-8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture as follows: A microwave vial wascharged with 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (300 mg, 1.29mmol), racemic2-[(1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(367 mg, 1.29 mmol), cesium carbonate (841 mg, 2.58 mmol), andPd(dppf)Cl₂CH₂Cl₂ (105 mg, 0.13 mmol). The solids were dissolved indioxane (4 mL) and H₂O (2 mL), and the mixture was degassed with N2. Thevial was sealed and heated to 120° C. for 1 h. The reaction mixture wasthen cooled and filtered through celite, washing with EtOAc. Thefiltrate was concentrated in vacuo, and the resulting residue purifiedby silica gel chromatography (0-100% EtOAc/hexanes), affording6-chloro-8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 310.10 [M+1].

Intermediate 104.6-chloro-8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 103, but replacing racemic2-[(1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith4,4,5,5-tetramethyl-2-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane.ES/MS m/z: 354.20 [M+1].

Intermediate 105.6-chloro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 103, but replacing racemic2-[(1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane.ES/MS m/z: 354.20 [M+1].

Intermediate 106.6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 103, but replacing racemic2-[(1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 350.20 [M+1].

Intermediate 107.4-(((1R,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrile(Racemic Mixture)

4-(((1R,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 103, but replacing racemic2-[(1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith4-(((1R,25)-2-(trifluoro-14-boraneyl)cyclopropyl)methyl)benzonitrile,potassium salt. ES/MS m/z: 309.10 [M+1].

Suzuki Cross Coupling with Cyclopropyl Boronic Acids Intermediate 108.6-chloro-2,8-dicyclopropyl-imidazo[1,2-b]pyridazine

6-chloro-2,8-dicyclopropyl-imidazo[1,2-b]pyridazine was prepared asfollows: A microwave vial was charged with8-bromo-6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazine (200 mg, 0.734mmol, 1 equiv), cyclopropylboronic acid (180 mg, 2.09 mmol, 2.85 equiv),cesium carbonate (478 mg, 1.47 mmol, 2 equiv), and Pd(dppf)Cl₂CH₂Cl₂ (60mg, 10 mol %). The reaction mixture was dissolved in 1:1 dioxane/H₂O (4mL total), purged with argon, and heated in a microwave reactor at 110°C. After 1.5 hour, the reaction mixture was then filtered and purifiedwith reverse phase HPLC (ACN/water with 0.1% TFA) to afford6-chloro-2,8-dicyclopropyl-imidazo[1,2-b]pyridazine. ES/MS m/z: 234.10[M+H].

Condensation of 3-amino pyridazine with Bromomethyl Aryl KetonesIntermediate 109.8-bromo-6-chloro-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine

A mixture of 4-bromo-6-chloropyridazin-3-amine (207.0 mg, 0.99 mmol, 1.0equiv.) and 2-bromo-1-(2-(trifluoromethyl)phenyl)ethan-1-one (647.7 mg,2.42 mmol, 2.5 equiv.) in MeCN (6.5 mL) in a sealed vessel was heated to80° C. After 24 h, the mixture was filtered through celite, rinsed withEtOAc, and the filtrate was concentrated in vacuo. Purification bycolumn chromatography (0-100% DCM in hexanes) afforded8-bromo-6-chloro-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 377.90 [M+H].

Intermediate 110.8-bromo-6-chloro-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine

To 4-bromo-6-chloropyridazin-3-amine (503.1 mg, 2.41 mmol, 1.0 equiv.)in EtOH (15 mL) was added 2-bromo-1-(pyridin-2-yl)ethan-1-onehydrobromide (1685.7 mg, 6.00 mmol, 2.5 equiv.) and the mixture washeated to 85° C. After 24 h, the mixture was concentrated in vacuo. Theresulting solids were triturated with MeOH and EtOAc, filtered, rinsedwith Et2O, and dried under vacuum. The solids were diluted with EtOAc,filtered, and rinsed with EtOAc and sat. NaHCO3(aq). The layers wereseparated and the organics were washed with brine (50 mL), dried overNa₂SO₄, and concentrated in vacuo to afford8-bromo-6-chloro-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine. ES/MS m/z:309.00 [M+H].

Intermediate 111.8-bromo-6-chloro-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine

8-bromo-6-chloro-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine was preparedas a in the manner described for Intermediate 110, but replacing2-bromo-1-(pyridin-2-yl)ethan-1-one hydrobromide with2-bromo-1-(pyridin-3-yl)ethan-1-one hydrobromide. ES/MS m/z: 309.00[M+H].

Intermediate 112.8-bromo-6-chloro-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine

8-bromo-6-chloro-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine was preparedas a in the manner described for Intermediate 110, but replacing2-bromo-1-(pyridin-2-yl)ethan-1-one hydrobromide with2-bromo-1-(pyridin-4-yl)ethan-1-one hydrobromide. ES/MS m/z: 309.00[M+H].

Negishi Cross Coupling with Cyclopropyl Zinc Bromide Intermediate 113.6-chloro-8-cyclopropyl-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine

To a solution of8-bromo-6-chloro-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine(163.9 mg, 0.43 mmol, 1.0 equiv.) and Pd(PPh₃)₄ (25.4 mg, 0.02 mmol,0.05 equiv.) in THF (1 mL) was added 0.5 M cyclopropylzinc bromide inTHF (1.3 mL, 0.65 mmol, 1.5 equiv.). After 21 h, the reaction wasquenched with sat. NaHCO₃(aq) (5 mL) and extracted with EtOAc (15 mL).The organics were washed with brine (10 mL), dried over Na₂SO₄, andconcentrated in vacuo. Purification by column chromatography (0-100%EtOAc in hexanes) afforded6-chloro-8-cyclopropyl-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 338.04 [M+H].

Intermediate 114.6-chloro-8-cyclopropyl-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine

6-chloro-8-cyclopropyl-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine wasprepared as a in the manner described for Intermediate 113, butreplacing8-bromo-6-chloro-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazinewith 8-bromo-6-chloro-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 271.10 [M+H].

Intermediate 115.6-chloro-8-cyclopropyl-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine

6-chloro-8-cyclopropyl-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine wasprepared as a in the manner described for Intermediate 113, butreplacing8-bromo-6-chloro-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazinewith 8-bromo-6-chloro-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 271.10 [M+H].

Intermediate 116.6-chloro-8-cyclopropyl-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine

6-chloro-8-cyclopropyl-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine wasprepared as a in the manner described for Intermediate 113, butreplacing8-bromo-6-chloro-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazinewith 8-bromo-6-chloro-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 271.10 [M+H].

Intermediate 117.8-((1S,2R)-2-benzylcyclopropyl)-6-chloroimidazo[1,2-b]pyridazine(Racemic Mixture)

8-((1S,2R)-2-benzylcyclopropyl)-6-chloroimidazo[1,2-b]pyridazine wasprepared as a racemic mixture as follows: A microwave vial was chargedwith 8-bromo-6-chloroimidazo[1,2-b]pyridazine (300 mg, 1.29 mmol, 1equiv), racemic potassium trans-(2-benzylcyclopropyl)trifluoroborate(169 mg, 1.29 mmol, 1 equiv), cesium carbonate (841 mg, 2.58 mmol, 2equiv), and Pd(dppf)Cl₂CH₂Cl₂ (94 mg, 10 mol %). The solids weredissolved in 2:1 dioxane/H₂O (5 mL), purged with argon, and heated at120° C. After 3 hours, the reaction mixture was directly purified bysilica gel chromatography (0-100% EtOAc/Hex), affording8-((1S,2R)-2-benzylcyclopropyl)-6-chloroimidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 284.10 [M+H].

Intermediate 118.6-chloro-8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture as follows: A microwave vial wascharged with 8-bromo-6-chloroimidazo[1,2-b]pyridazine (200 mg, 0.86mmol, 1 equiv), racemic2-((1S,2S)-2-(3,3-difluorocyclobutyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(222 mg, 0.86 mmol, 1 equiv), cesium carbonate (561 mg, 1.72 mmol, 2equiv), and Pd(dppf)Cl₂CH₂Cl₂ (63 mg, 10 mol %). The solids weredissolved in 2:1 dioxane/H₂O (4 mL), purged with argon, and heated at120° C. After 14 hours, the reaction mixture was directly purified bysilica gel chromatography (0-100% EtOAc/Hex), affording6-chloro-8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 283.70 [M+H].

Intermediate 119.6-chloro-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture as follows: A microwave vial wascharged with 8-bromo-6-chloroimidazo[1,2-b]pyridazine (80 mg, 0.34 mmol,1 equiv), racemic6-methyl-2-((1S,2S)-2-(trifluoromethyl)cyclopropyl)-1,3,6,2-dioxazaborocane-4,8-dione(100 mg, 0.38 mmol, 1.1 equiv), potassium carbonate (143 mg, 1.03 mmol,3 equiv), palladium(II) acetate (7.7 mg, 10 mol %), and RuPhos (32 mg,20 mol %). The solids were dissolved in 3:1 Toluene/H₂O (2 mL), purgedwith argon, and heated at 115° C. After 20 hours, the reaction mixturewas directly purified by silica gel chromatography (0-80% EtOAc/CH₂Cl₂),affording6-chloro-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 262.10 [M+H].

Intermediate 120.6-chloro-8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture as follows: A microwave vial wascharged with 8-bromo-6-chloroimidazo[1,2-b]pyridazine (300 mg, 1.29mmol, 1 equiv),2-(2-fluoro-2-phenylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(338 mg, 1.29 mmol, 1 equiv), cesium carbonate (841 mg, 2.58 mmol, 2equiv), and Pd(dppf)Cl₂CH₂Cl₂ (94 mg, 10 mol %). The solids weredissolved in 2:1 dioxane/H₂O (4 mL), purged with argon, and heated at120° C. After 2 hours, the reaction mixture was directly purified bysilica gel chromatography (0-100% EtOAc/Hex), affording6-chloro-8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 288.10 [M+H].

Suzuki Cross Coupling Reaction with (2,4-dimethoxypyrimidin-5-yl)boronicacid

Intermediate 121.8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine

8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(4,4-difluorocyclohexyl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 391.1 [M+1].

Intermediate 122.8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile

8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazine-3-carbonitrile.ES/MS m/z: 401.1 [M+1].

Intermediate 123.8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-imidazo[1,2-b]pyridazine

8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-imidazo[1,2-b]pyridazine.ES/MS m/z: 390.1 [M+1].

Intermediate 124.8-((benzyloxy)methyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((benzyloxy)methyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with8-((benzyloxy)methyl)-6-chloroimidazo[1,2-b]pyridazine. ES/MS m/z:378.18 [M+H].

Intermediate 125.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MS m/z:389.1 [M+1].

Intermediate 126.8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 410.1 [M+1].

Intermediate 127.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 428.1 [M+1].

Intermediate 128.4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile

4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile.ES/MS m/z: 417.1 [M+1].

Intermediate 129.6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 381.1 [M+1].

Intermediate 130.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 341.2 [M+1].

Intermediate 131.5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile(Racemic Mixture)

5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile.ES/MS m/z: 417.1 [M+1].

Intermediate 132.8-[(1S,2S)-2-(2,5-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-(2,5-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(2,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 410.2 [M+1].

Intermediate 133.6-(2,4-dimethoxypyrimidin-5-yl)-8-(2-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(2-phenylazetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(2-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MS m/z:389.1 [M+1].

Intermediate 134.8-cyclopropyl-6-(2,4-dimethoxy-pyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine

8-cyclopropyl-6-(2,4-dimethoxy-pyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared as follows: A microwave vial was charged with(2,4-dimethoxypyrimidin-5-yl)boronic acid (143 mg, 0.78 mmol, 1.1equiv), Pd(dppf)Cl₂—CH₂Cl₂ (52 mg, 10 mol %), Cs₂CO₃ (462 mg, 1.42 mmol,2 equiv) and 6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine(150 mg, 0.709 mmol, 1 equiv). The reaction mixture was dissolved in 3:1dioxane/H₂O (4 mL), purged with argon, and was stirred at 80° C. for 3h. The reaction mixture was then filtered and purified with reversephase HPLC (ACN/water with 0.1% TFA) to afford8-cyclopropyl-6-(2,4-dimethoxy-pyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 316.10 [M+H].

Intermediate 135.8-(4,4-difluoro-1-piperidyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(4,4-difluoro-1-piperidyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-(4,4-difluoro-1-piperidyl)imidazo[1,2-b]pyridazine. ES/MSm/z: 377.10 [M+H].

Intermediate 136.8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 391.20 [M+H].

Intermediate 137.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 355.20 [M+H].

Intermediate 138.8-[(3S,4S)-3,4-difluoropyrrolidin-1-0]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 363.20 [M+H].

Intermediate 139.8-[(3S,4R)-3,4-difluoropyrrolidin-1-0]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Cis)

8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(cis) was prepared in the manner described for Intermediate 134, butreplacing 6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazine(cis). ES/MS m/z: 363.20 [M+H].

Intermediate 140.6-(2,4-dimethoxypyrimidin-5-yl)-8-pyrazol-1-yl-imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-pyrazol-1-yl-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-pyrazol-1-yl-imidazo[1,2-b]pyridazine. ES/MS m/z: 324.10[M+H].

Intermediate 141.8-(3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 363.10 [M+H].

Intermediate 142.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 375.20 [M+H].

Intermediate 143.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 442.10 [M+H].

Intermediate 144.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 442.10 [M+H].

Intermediate 145.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 424.20 [M+H].

Intermediate 146.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 410.10 [M+H].

Intermediate 147.N-(cyclopropylmethyl)-4-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]aniline

N-(cyclopropylmethyl)-4-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]anilinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-N-(cyclopropylmethyl)aniline.ES/MS m/z: 403.20 [M+H].

Intermediate 148.2,8-dicyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

2,8-dicyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-2,8-dicyclopropyl-imidazo[1,2-b]pyridazine. ES/MS m/z: 338.20[M+H].

Intermediate 149.3-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-fluoro-benzonitrile

3-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-fluoro-benzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with3-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-5-fluoro-benzonitrile(racemic mixture). ES/MS m/z: 417.10 [M+H].

Intermediate 150.2-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine

2-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-2-cyclopropyl-8-[(1R,2R)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 432.10 [M+H].

Intermediate 151.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1R,2R)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 392.10 [M+H].

Intermediate 152.8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine

8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 428.10 [M+H].

Intermediate 153.6-(2,4-dimethoxypyrimidin-5-yl)-8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazine. ES/MSm/z: 369.20 [M+H].

Intermediate 154.8-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine

8-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 428.20 [M+H].

Intermediate 155.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 375.10 [M+H].

Intermediate 156.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 375.10 [M+H].

Intermediate 157.5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine. ES/MSm/z: 355.16 [M+H].

Intermediate 158.5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 356.20 [M+H].

Intermediate 159.8-(3,3-difluoropiperidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3,3-difluoropiperidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoropiperidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 377.17 [M+H].

Intermediate 160. 8-(3-azabicyclo[3.2.1]octan-3-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

Bicyclo[3.2.1]octan-3-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with8-(3-azabicyclo[3.2.1]octan-3-yl)-6-chloroimidazo[1,2-b]pyridazine.ES/MS m/z: 367.14 [M+H].

Intermediate 161.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with racemic6-chloro-8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 460.10 [M+H].

Intermediate 162.8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine

8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-cyclopropyl-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 442.10 [M+H].

Intermediate 163.8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine

8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-4-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-cyclopropyl-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 375.10 [M+H].

Intermediate 164.8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with racemic6-chloro-8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 426.10 [M+H].

Intermediate 165.8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with racemic6-chloro-8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 426.10 [M+H].

Intermediate 166.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with racemic6-chloro-8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 460.10 [M+H].

Intermediate 167.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with racemic6-chloro-8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 404.20 [M+H].

Intermediate 168.8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine

8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-3-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-cyclopropyl-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 375.19 [M+H].

Intermediate 169.8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine

8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-2-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-cyclopropyl-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 375.20 [M+H].

Intermediate 170.8-((1S,2R)-2-benzylcyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2R)-2-benzylcyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with8-((1S,2R)-2-benzylcyclopropyl)-6-chloroimidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 388.20 [M+H].

Intermediate 171.8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 388.10 [M+H].

Intermediate 172.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 366.10 [M+H].

Intermediate 173.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 392.20 [M+H].

Intermediate 174.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared as follows: To a mixture of6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine(24 mg, 0.082 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (30mg, 0.16 mmol) in 1,4-dioxane (1.5 mL) and water (0.75 mL) were addedferrous; cyclopenta-2,4-dien-1-yl(diphenyl)phosphane; dichloromethane;dichloropalladium (7 mg, 0.008 mmol) and cesium carbonate (53 mg, 0.16mmol). The reaction mixture was heated at 80° C. for 1 h. The reactionmixture was then filtered and was purified with Prep HPLC to afford6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 399.10 [M+H].

Intermediate 175.8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 414.20 [M+1].

Intermediate 176.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 458.20 [M+1].

Intermediate 177.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 458.20 [M+1].

Intermediate 178.8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 454.20 [M+1].

Intermediate 179.4-(((1R,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrile

4-(((1R,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrilewas prepared in the manner described for Intermediate 174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith4-(((1R,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrile.ES/MS m/z: 413.20 [M+1].

Synthesis of Heterocycles Via Pyridazine Cyclization Intermediate 180.(Z)—N-(4-bromo-6-chloropyridazin-3-yl)-N′-hydroxyformimidamide

To a mixture of 4-bromo-6-chloro-pyridazin-3-amine (200 mg, 0.959 mmol)in dry iPrOH (2 mL) was added N,N-dimethylformamide dimethyl acetal(0.332 mL, 2.49 mmol). The mixture was heated to 80° C. and stirred for3 h. The mixture was then cooled to rt, and hydroxylamine hydrochloride(100 mg, 1.44 mmol) was added. The mixture was heated to 50° C. andstirred for another 3 h. The reaction mixture was quenched with 10%NaHCO₃ solution and extracted with 2-MeTHF (2×5 mL). Combined organicswere dried over MgSO₄, filtered, and concentrated in vacuo. Theresulting residue was purified by silica gel chromatography (0-100%EtOAc/hexanes) to affordN-(4-bromo-6-chloropyridazin-3-yl)-N′-hydroxyformimidamide. ES/MS m/z:251.0 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.39 (d, J=1.2Hz, 1H), 8.24 (d, J=9.6 Hz, 1H), 8.04 (d, J=9.4 Hz, 1H).

Intermediate 181. 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine

To a mixture ofN-(4-bromo-6-chloropyridazin-3-yl)-N′-hydroxyformimidamide (44 mg, 0.175mmol) in THF (0.5 mL) was added T3P (50% in EtOAc, 0.156 mL, 0.262mmol). The mixture was heated to 55° C. and stirred for 2 h. The mixturewas quenched with 10% NaHCO₃ solution and extracted with EtOAc (2×5 mL).Combined organics were dried over MgSO₄, filtered, and concentrated invacuo. The resulting residue was purified by silica gel chromatography(0-100% EtOAc/hexanes) to afford8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine. ES/MS m/z: 233.0[M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.41 (s, 1H).

Intermediate 182.6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine

To a mixture of 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine (37mg, 0.158 mmol) and 7,7-difluoro-5-azaspiro[2.4]heptane (23 mg, 0.174mmol) in MeCN (1 mL) was added N,N-diisopropylethylamine (0.036 mL,0.206 mmol). The mixture was stirred for 30 min at rt, then heated to40° C. and stirred for 1 h. The mixture was then concentrated in vacuoand the resulting residue was purified by silica gel chromatography(0-100% EtOAc/hexanes) to afford6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 286.1 [M+1].

Intermediate 183.6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine

A solution of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (250 mg, 1.08mmol), 7,7-difluoro-5-azaspiro[2.4]heptane hydrochloride (158 mg, 1.18mmol), and N,N-diisopropylethylamine (0.22 mL, 1.29 mmol) in MeCN (3 mL)was heated to 85° C. After 2 hours, the reaction mixture was directlypurified by SiO₂ chromatography (0-80% EtOAc/Hex),6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 285.10 [M+H].

Intermediate 184.6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 59, but replacing3,3-dimethylpyrrolidine hydrochloride with3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride and8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 305.10[M+H].

Intermediate 185.6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine (250 mg,1 mmol, 1 equiv), 7,7-difluoro-5-azaspiro[2.4]heptane hydrochloride (146mg, 1.1 mmol, 1.1 equiv), and N,N-diisopropylethylamine (0.42 mL, 2.4mmol, 2.4 equiv) in MeCN (5 mL, 0.2M) was heated to 85° C. After 7hours, the reaction mixture was directly purified by SiO₂ chromatography(0-80% EtOAc/Hex), affording6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 303.10 [M+H].

Intermediate 186.8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine

8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 390.2 [M+1].

Intermediate 187.8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 389.20 [M+H].

Intermediate 188.8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine

8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 134, but replacing6-chloro-8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 409.20 [M+H].

Intermediate 189.8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 407.20 [M+H].

Intermediate 190. 6-bromo-1-(2,2-difluoroethyl)indazole

To a solution of 6-bromo-1H-indazole (1 g, 5.05 mmol, 1 equiv) in DMF(20 mL) was added potassium carbonate (2104 mg, 15.2 mmol, 3 equiv) and2,2-difluoroethyl trifluoromethanesulfonate (1.63 g, 7.61 mmol, 1.5equiv). The reaction mixture was heated to 80° C. After 2 hours, thereaction mixture was diluted with brine (50 mL) and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording 6-bromo-1-(2,2-difluoroethyl)indazole.ES/MS m/z: 261.10 [M+H].

Intermediate 191. 6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)indazole

To a solution of 6-bromo-3-fluoro-1H-indazole (0.59 g, 2.74 mmol, 1equiv) in DMF (4 mL) was added potassium carbonate (1138 mg, 8.23 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (955 mg,4.12 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 1hour, the reaction mixture was diluted with brine (50 mL) and extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. Purification was accomplished by SiO₂chromatography (0-50% EtOAc/Hex), affording6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)indazole. ES/MS m/z: 297.10[M+H].

Intermediate 192. 6-bromo-1-(2,2-difluoroethyl)-7-fluoro-indazole

To a solution of 6-bromo-1-(2,2-difluoroethyl)indazole (0.3 g, 1.15mmol, 1 equiv) in ACN (5 mL) and acetic acid (0.25 mL) was addedN-Fluoro-N′-chloromethyltriethylenediamine (814 mg, 2.3 mmol, 2 equiv).The reaction mixture was heated to 90° C. After 16 hours, the reactionmixture was directly purified by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier). Pure fractions were combined and concentrated. Residueobtained was diluted with water, neutralized with aqueous sodium sulfateand extracted with DCM. Organic layer was separated, dried over sodiumsulfate, filtered and concentrated. Solids obtained was dried at highvacuum overnight affording6-bromo-1-(2,2-difluoroethyl)-7-fluoro-indazole. ES/MS m/z: 279.10[M+H].

Intermediate 193. 6-bromo-3-fluoro-1H-indazole

To a solution of 6-bromo-1H-indazole (4.4 g, 22.3 mmol, 1 equiv) in ACN(60 mL) and acetic acid (3 mL) was addedN-Fluoro-N′-chloromethyltriethylenediamine (15.82 g, 44.7 mmol, 2equiv). The reaction mixture was heated to 90° C. After 16 hours, thereaction mixture was directly purified by RP-HPLC (10-90% MeCN/H₂O withTFA modifier). Pure fractions were combined and concentrated. Residueobtained was diluted with water, neutralized with aqueous sodium sulfateand extracted with DCM. Organic layer was separated, dried over sodiumsulfate, filtered and concentrated. Solids obtained was dried at highvacuum overnight affording 6-bromo-3-fluoro-1H-indazole. ES/MS m/z:215.00 [M+H].

Intermediate 194. 6-bromo-2-(cyclopropylmethyl)indazole

To a solution of 6-bromo-1H-indazole (1 g, 5.05 mmol, 1 equiv) in DMF(20 mL) was added potassium carbonate (2104 mg, 15.2 mmol, 3 equiv) andbromomethylcyclopropane (1.03 g, 7.61 mmol, 1.5 equiv). The reactionmixture was heated to 80° C. After 2 hours, the reaction mixture wasdiluted with brine (50 mL) and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-100% EtOAc/Hex),affording 6-bromo-1-(cyclopropylmethyl)indazole. ES/MS m/z: 251.10[M+H].

Intermediate 195. 6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridine

To a solution of 6-bromo-1H-pyrrolo[3,2-c]pyridine (1 g, 5.08 mmol, 1equiv) in DMF (20 mL) was added potassium carbonate (2104 mg, 15.2 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.77 g,7.61 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 2hours, the reaction mixture was diluted with brine (50 mL) and extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. Purification was accomplished by SiO₂chromatography (0-100% EtOAc/Hex), affording6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridine. ES/MS m/z:279.00 [M-FH].

Intermediate 196. 6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridine

To a solution of 6-bromo-1H-pyrrolo[2,3-b]pyridine (1 g, 5.08 mmol, 1equiv) in DMF (20 mL) was added potassium carbonate (2104 mg, 15.2 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.77 g,7.61 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 2hours, the reaction mixture was diluted with brine (50 mL) and extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. Purification was accomplished by SiO₂chromatography (0-100% EtOAc/Hex), affording6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridine. ES/MS m/z:279.00 [M+H].

Intermediate 197. 6-bromo-3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazole

To a solution of 6-bromo-3-cyclopropyl-1H-indazole (1 g, 4.22 mmol, 1equiv) in DMF (20 mL) was added potassium carbonate (1749 mg, 12.7 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.77 g,7.61 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 3hours, the reaction mixture was diluted with brine (50 mL) and extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. Purification was accomplished by SiO₂chromatography (0-100% EtOAc/Hex), affording6-bromo-3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazole. ES/MS m/z:319.20 [M+H].

Intermediate 198. 6-bromo-2-[(2,2-difluorocyclopropyl)methyl]indazole

To a solution of 6-bromo-1H-indazole (0.5 g, 2.54 mmol, 1 equiv) in DMF(8 mL) was added potassium carbonate (877 mg, 6.34 mmol, 2.5 equiv) and2-(bromomethyl)-1,1-difluorocyclopropane (521 mg, 3.05 mmol, 1.2 equiv).The reaction mixture was heated to 80° C. After 3 hours, the reactionmixture was diluted with brine (50 mL) and extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-bromo-2-[(2,2-difluorocyclopropyl)methyl]indazole. ES/MS m/z: 287.00[M-FH].

Intermediate 199.6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridine

To a solution of 6-bromo-3-fluoro-1H-pyrrolo[3,2-c]pyridine (0.5 g, 2.33mmol, 1 equiv) in DMF (8 mL) was added potassium carbonate (964 mg, 6.98mmol, 3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1767mg, 7.61 mmol, 1.5 equiv). The reaction mixture was heated to 80° C.After 3 hours, the reaction mixture was diluted with brine (50 mL) andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. Purification was accomplished bySiO₂ chromatography (0-100% EtOAc/Hex), affording6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridine. ES/MSm/z: 297.00 [M+H].

Intermediate 200. 6-bromo-3-isopropyl-1-(2,2,2-trifluoroethyl)indazole

To a solution of 6-bromo-3-isopropyl-1H-indazole (0.5 g, 2.09 mmol, 1equiv) in DMF (8 mL) was added potassium carbonate (867 mg, 6.27 mmol, 3equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (883 mg, 3.81mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 3hours, the reaction mixture was diluted with brine (50 mL) and extractedwith EtOAc. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. Purification was accomplished by SiO₂chromatography (0-100% EtOAc/Hex), affording6-bromo-3-isopropyl-1-(2,2,2-trifluoroethyl)indazole. ES/MS m/z: 321.20[M+H].

Intermediate 201. 6-bromo-4-(2,2,2-trifluoroethoxy)isoquinoline

To a solution of 6-bromoisoquinolin-4-ol (0.5 g, 2.23 mmol, 1 equiv) inDMF (5 mL) was added potassium carbonate (925 mg, 6.69 mmol, 3 equiv)and 2,2,2-trifluoroethyl trifluoromethanesulfonate (777 mg, 3.35 mmol,1.5 equiv). The reaction mixture was heated to ° C. After 3 hours, thereaction mixture was diluted with brine (50 mL) and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-bromo-4-(2,2,2-trifluoroethoxy)isoquinoline. ES/MS m/z: 306.00 [M+H];¹H NMR (400 MHz, Chloroform-d) δ 8.98 (s, 1H), 8.42-8.37 (m, 1H), 8.13(s, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.78 (dd, J=8.7, 1.9 Hz, 1H), 4.63 (q,J=7.9 Hz, 2H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −74.28 (t, J=7.9 Hz).

Intermediate 202. 6-bromo-4-(2,2,2-trifluoroethoxy)quinoline and6-bromo-1-(2,2,2-trifluoroethyl)quinolin-4-one

To a solution of 6-bromoquinolin-4-ol (1 g, 4.46 mmol, 1 equiv) in DMF(10 mL) was added potassium carbonate (1851 mg, 13.4 mmol, 3 equiv) and2,2,2-trifluoroethyl trifluoromethanesulfonate (1554 mg, 6.69 mmol, 1.5equiv). The reaction mixture was heated to 80° C. After 3 hours, thereaction mixture was diluted with brine (50 mL) and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording 6-bromo-4-(2,2,2-trifluoroethoxy)quinolineES/MS m/z: 306.00 [M-FH]; 1H NMR (400 MHz, Chloroform-d) δ 8.82 (d,J=5.1 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.84 (dd,J=9.0, 2.2 Hz, 1H), 6.76 (d, J=5.1 Hz, 1H), 4.61 (q, J=7.8 Hz, 2H); 19FNMR (376 MHz, Chloroform-d) δ −73.90 (t, J=7.9 Hz) and6-bromo-1-(2,2,2-trifluoroethyl)quinolin-4-one ES/MS m/z: 306.00 [M+H];¹H NMR (400 MHz, Chloroform-d) δ 8.60 (d, J=2.4 Hz, 1H), 7.79 (dd,J=9.1, 2.4 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.32 (d, J=9.1 Hz, 1H), 6.37(d, J=7.9 Hz, 1H), 4.65 (q, J=8.0 Hz, 2H); ¹⁹F NMR (376 MHz,Chloroform-d) δ −70.63 (t, J=8.0 Hz).

Intermediate 203. 7-bromo-2-(2,2,2-trifluoroethyl)isoquinolin-1-one

To a solution of 7-bromoisoquinolin-1-ol (1 g, 4.46 mmol, 1 equiv) inDMF (10 mL) was added potassium carbonate (1851 mg, 13.4 mmol, 3 equiv)and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1554 mg, 6.69 mmol,1.5 equiv). The reaction mixture was heated to 80° C. After 3 hours, thereaction mixture was diluted with brine (50 mL) and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording7-bromo-2-(2,2,2-trifluoroethyl)isoquinolin-1-one. ES/MS m/z: 306.00[M+H]; ¹H NMR (400 MHz, Chloroform-d) δ 8.60 (d, J=2.1 Hz, 1H), 7.79(dd, J=8.5, 2.2 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.10 (dd, J=7.4, 1.1Hz, 1H), 6.53 (d, J=7.5 Hz, 1H), 4.68 (q, J=8.6 Hz, 2H); ¹⁹F NMR (376MHz, Chloroform-d) δ −71.09 (t, J=8.7 Hz).

Intermediate 204.6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one

To a solution of 6-bromo-3,3-dimethyl-indolin-2-one (0.877 g, 3.65 mmol,1 equiv) in DMF (10 mL) was added potassium carbonate (1514 mg, 11 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1450 mg,6.25 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After20 hours, the reaction mixture was diluted with brine (50 mL) andextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. Purification was accomplished bySiO₂ chromatography (0-100% EtOAc/Hex), affording 76-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one. ES/MS m/z:322.00 [M+H]

Intermediate 205.6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one

To a solution of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one(0.5 g, 2.07 mmol, 1 equiv) in DMF (4 mL) was added potassium carbonate(860 mg, 6.22 mmol, 3 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (722 mg, 3.11 mmol, 1.5 equiv). The reactionmixture was heated to 80° C. After 2 hours, the reaction mixture wasdiluted with brine (50 mL) and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-100% EtOAc/Hex),affording6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one.ES/MS m/z: 323.00 [M+H]

Intermediate 206.6-chloro-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-one

To a solution of 6-chloro-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2-one(0.25 g, 1.27 mmol, 1 equiv) in DMF (8 mL) was added potassium carbonate(527 mg, 3.81 mmol, 3 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (443 mg, 1.91 mmol, 1.5 equiv). The reactionmixture was heated to 80° C. After 2 hours, the reaction mixture wasdiluted with brine (50 mL) and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-100% EtOAc/Hex),affording6-chloro-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-one.ES/MS m/z: 279.10 [M+H]

Intermediate 207. N-(4,4-difluoropyrrolidin-3-yl)acetamide;Hydrochloride

To an ice cold solution of tert-butyl4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.1 g, 0.45 mmol, 1equiv) in DCM (2 mL) was added N,N-Diisopropylethylamine (0.086 mL,mmol, 1.1 equiv) and acetyl chloride (0.035 mL, 0.495 mmol, 1.1 equiv).After stirring at ° C. for 20 min, the reaction mixture was treated with4M HCl/dioxane (10 mL) and was further stirred for 4 h at roomtemperature. The reaction mixture was concentrated and residue obtainedwas dried at high vacuum overnight to affordN-(4,4-difluoropyrrolidin-3-yl)acetamide; hydrochloride. ES/MS m/z:201.20 [M+H].

Intermediate 208. 2,2,2-trifluoroethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; Hydrochloride

To an ice cold solution of tert-butyl4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.258 g, 1.16 mmol, 1equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.243 mL, 1.39mmol, 1.2 equiv) and 2,2,2-trifluoroethyl carbonochloridate (0.201 g,1.24 mmol, 1.07 equiv). After stirring at 0° C. for 20 min, the reactionmixture was purified by SiO₂ chromatography (0-50% EtOAc/Hex). Fractionswere combined and concentrated. The residue obtained was treated with 4MHCl/dioxane (10 mL) and was further stirred for 8h at room temperature.The reaction mixture was concentrated and was dried at high vacuumovernight to afford 2,2,2-trifluoroethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride. ES/MS m/z:249.10 [M+H].

Intermediate 209. cyclopropylmethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; Hydrochloride

To an ice cold solution of tert-butyl4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.25 g, 1.12 mmol, 1equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.24 mL, 1.35mmol, 1.2 equiv) and cyclopropylmethyl carbonochloridate (0.167 g, 1.24mmol, 1.1 equiv). After stirring at 0° C. for 20 min, the reactionmixture was purified by SiO₂ chromatography (0-50% EtOAc/Hex). Fractionswere combined and concentrated. The residue obtained was treated with 4MHCl/dioxane (10 mL) and was further stirred for 8h at room temperature.The reaction mixture was concentrated and was dried at high vacuumovernight to afford cyclopropylmethyl N-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride. ES/MS m/z: 221.10 [M+H].

Intermediate 210. 2,2-difluoroethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; Hydrochloride

To an ice cold solution of tert-butyl4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.285 g, 1.28 mmol, 1equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.29 mL, 1.67mmol, 1.3 equiv) and 2,2-difluoroethyl carbonochloridate (0.222 g, 1.54mmol, 1.2 equiv). After stirring at 0° C. for 20 min, the reactionmixture was purified by SiO₂ chromatography (0-50% EtOAc/Hex). Fractionswere combined and concentrated. The residue obtained was treated with 4MHCl/dioxane (10 mL) and was further stirred for 8h at room temperature.The reaction mixture was concentrated and was dried at high vacuumovernight to afford 2,2-difluoroethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride. ES/MS m/z:231.10 [M+H].

Intermediate 211. N-(4,4-difluoropyrrolidin-3-yl)benzamide;Hydrochloride

To an ice cold solution of tert-butyl4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.1 g, 0.45 mmol, 1equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.09 mL, mmol,1.1 equiv) and benzoyl chloride (0.07 g, 0.5 mmol, 1.1 equiv). Afterstirring at 0° C. for 20 min, the reaction mixture was purified by SiO₂chromatography (0-50% EtOAc/Hex). Fractions were combined andconcentrated. The residue obtained was treated with 4M HCl/dioxane (10mL) and was further stirred for 8h at room temperature. The reactionmixture was concentrated and was dried at high vacuum overnight toafford N-(4,4-difluoropyrrolidin-3-yl)benzamide; hydrochloride. ES/MSm/z: 227.20 [M+H].

Intermediate 212.N-(4,4-difluoropyrrolidin-3-yl)-4-(trifluoromethyl)benzamide;Hydrochloride

To an ice cold solution of tert-butyl4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.175 g, 0.79 mmol, 1equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.15 mL, mmol,1.1 equiv) and 4-(trifluoromethyl)benzoyl chloride (0.18 g, 0.87 mmol,1.1 equiv). After stirring at 0° C. for 20 min, the reaction mixture waspurified by SiO₂ chromatography (0-50% EtOAc/Hex). Fractions werecombined and concentrated. The residue obtained was treated with 4MHCl/dioxane (10 mL) and was further stirred for 8h at room temperature.The reaction mixture was concentrated and was dried at high vacuumovernight to affordN-(4,4-difluoropyrrolidin-3-yl)-4-(trifluoromethyl)benzamide;hydrochloride. ES/MS m/z: 295.10 [M+H].

Intermediate 213.N-(4,4-difluoropyrrolidin-3-yl)-5-(trifluoromethyl)pyridine-2-carboxamide;Hydrochloride

To an ice cold solution of tert-butyl4-amino-3,3-difluoro-pyrrolidine-1-carboxylate (0.2 g, 0.9 mmol, 1equiv) in DCM (5 mL) was added N,N-Diisopropylethylamine (0.17 mL, mmol,1.1 equiv) and 5-(trifluoromethyl)pyridine-2-carbonyl chloride (0.18 g,0.87 mmol, equiv). After stirring at 0° C. for 20 min, the reactionmixture was purified by SiO₂ chromatography (0-70% EtOAc/Hex). Fractionswere combined and concentrated. The residue obtained was treated with 4MHCl/dioxane (10 mL) and was further stirred for 8h at room temperature.The reaction mixture was concentrated and was dried at high vacuumovernight to affordN-(4,4-difluoropyrrolidin-3-yl)-5-(trifluoromethyl)pyridine-2-carboxamide;hydrochloride. ES/MS m/z: 296.10 [M+H].

Intermediate 214.6-bromo-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridine

To a solution of 6-bromo-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(0.5 g, 1.89 mmol, 1 equiv) in DMF (4 mL) was added potassium carbonate(782 mg, 5.66 mmol, 3 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.66 g, 2.83 mmol, 1.5 equiv). The reactionmixture was heated to 80° C. After 3 hours, the reaction mixture wasdiluted with brine (50 mL) and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-100% EtOAc/Hex),affording6-bromo-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridine.¹H NMR (400 MHz, Chloroform-d) δ 7.95 (dt, J=8.3, 0.8 Hz, 1H), 7.63 (s,1H), 7.45 (d, J=8.3 Hz, 1H), 4.94 (q, J=8.5 Hz, 2H). ¹⁹F NMR (376 MHz,Chloroform-d) δ −58.46-71.77 (t, J=8.6 Hz).

Intermediate 215.4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile

Step 1: To a cooled (0° C.) solution of 4-vinylbenzonitrile (1000 mg,7.74 mmol, 1 equiv) and Ru(II)-(R)-Pheox catalyst[Tetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2-oxazolyl-N]phenyl]ruthenium(II)Hexafluorophosphate] (49 mg, 1 mol %) in CH₂Cl₂ (78 mL, was added a 0.2Msolution of 1,3-dioxoisoindolin-2-yl 2-diazoacetate (1969 mg, 8.52 mmol,1.1 equiv) in CH₂Cl₂ over 40 minutes. After an additional 3 hours at 0°C., the reaction mixture was diluted with MeOH (5 mL) and concentratedto ˜10 mL. Purification was accomplished by SiO₂ chromatography (0-70%EtOAc/Hex), affording (1,3-dioxoisoindolin-2-yl)(1S,2S)-2-(4-cyanophenyl)cyclopropanecarboxylate. ES/MS m/z: 333.10[M+H].

Step 2: To a solution of 1 (1,3-dioxoisoindolin-2-yl)(1S,2S)-2-(4-cyanophenyl)cyclopropanecarboxylate (1140 mg, 3.43 mmol, 1equiv) in EtOAc (15 mL) was added B2Pin2 (1742 mg, 6.86 mmol, 2 equiv)and methyl isonicotinate (0.2 mL, 1.72 mmol, 0.5 equiv). The resultingmixture was heated to 80° C. under an atmosphere of argon. After 16hours, the reaction mixture was filtered, concentrated, and purified bySiO₂ chromatography (0-40% EtOAc/Hex), affording4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile.ES/MS m/z: 270.10 [M+H].

Intermediate 216.3,3-dimethyl-6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)indolin-2-one

Step 1: 6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one (2000mg, 6.21 mmol, 1 equiv), vinyl trifluoroborate (873 mg, 6.52 mmol, 1.05equiv), potassium carbonate (1890 mg, 13.7 mmol, 2.2 equiv), and(dppf)PdCl₂—CH₂Cl₂ (454 mg, 10 mol %) in 9:1 THF/H₂O (10 mL) was heatedto 85° C. After 20 hours, the reaction mixture was cooled to roomtemperature and purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording3,3-dimethyl-1-(2,2,2-trifluoroethyl)-6-vinyl-indolin-2-one. ES/MS m/z:270.10 [M+H].

Step 2: To a cooled (0° C.) solution of3,3-dimethyl-1-(2,2,2-trifluoroethyl)-6-vinyl-indolin-2-one (1425 mg,5.29 mmol, 1 equiv) and Ru(II)-(R)-Pheox catalyst[Tetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2-oxazolyl-N]phenyl]ruthenium(II)Hexafluorophosphate] (167 mg, 5 mol %) in CH₂Cl₂ (30 mL) was added a0.2M solution of 1,3-dioxoisoindolin-2-yl 2-diazoacetate (1346 mg, 5.82mmol, 1.1 equiv) in CH₂Cl₂ over 3 h. After an additional 1 hour at 0°C., the reaction mixture was diluted with MeOH (1 mL) and concentratedto ˜10 mL. Purification was accomplished by SiO₂ chromatography (0-100%EtOAc/Hex), affording (1,3-dioxoisoindolin-2-yl)(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropanecarboxylate.ES/MS m/z: 473.20 [M+H].

Step 3: To a solution of 1 (1,3-dioxoisoindolin-2-yl)(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropanecarboxylate(2318 mg, 4.91 mmol, 1 equiv) in EtOAc (25 mL) was added B2Pin2 (1869mg, 7.36 mmol, 1.5 equiv) and methyl isonicotinate (0.29 mL, 2.45 mmol,0.5 equiv). The resulting mixture was heated to 80° C. under anatmosphere of argon. After 4 hours, the reaction mixture was filtered,concentrated, and purified by SiO₂ chromatography (0-50% EtOAc/Hex),affording3,3-dimethyl-6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)indolin-2-one.ES/MS m/z: 410.20 [M+H].

Intermediate 217.3-fluoro-6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)indazole

Step 1: 6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)indazole (1420 mg, 4.78mmol, 1 equiv), vinyl trifluoroborate (672 mg, 5.02 mmol, 1.05 equiv),potassium carbonate (1450 mg, 10.5 mmol, 2.2 equiv), and(dppf)PdCl₂—CH₂Cl₂ (350 mg, 10 mol %) in 9:1 THF/H₂O (10 mL) was heatedto 85° C. After 20 hours, the reaction mixture was cooled to roomtemperature and purification was accomplished by SiO₂ chromatography(0-50% EtOAc/Hex), affording3-fluoro-1-(2,2,2-trifluoroethyl)-6-vinyl-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 7.65 (d, J=8.5 Hz, 1H), 7.39 (dd, J=8.4, 1.2 Hz, 1H),7.29 (d, J=2.0 Hz, 1H), 6.86 (dd, J=17.5, 10.9 Hz, 1H), 5.91 (d, J=17.5Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 4.79 (qd, J=8.3, 1.0 Hz, 2H). ¹⁹F NMR(376 MHz, Chloroform-d) δ −71.42 (t, J=8.3 Hz), −132.61.

Step 2: To a cooled (0° C.) solution of3-fluoro-1-(2,2,2-trifluoroethyl)-6-vinyl-indazole (780 mg, 3.19 mmol, 1equiv) and Ru(II)-(R)-Pheox catalyst[Tetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2-oxazolyl-N]phenyl]ruthenium(II)Hexafluorophosphate] (101 mg, 5 mol %) in CH₂Cl₂ (18 mL) was added a0.2M solution of 1,3-dioxoisoindolin-2-yl 2-diazoacetate (812 mg, 3.51mmol, 1.1 equiv) in CH₂Cl₂ over 2 h. After an additional 1 hour at 0°C., the reaction mixture was diluted with MeOH (1 mL) and concentratedto ˜10 mL. Purification was accomplished by SiO₂ chromatography (0-100%EtOAc/Hex), affording (1,3-dioxoisoindolin-2-yl)(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropanecarboxylate.ES/MS m/z: 448.20 [M+H].

Step 3: To a solution of (1,3-dioxoisoindolin-2-yl)(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropanecarboxylate(1328 mg, 2.97 mmol, 1 equiv) in EtOAc (12 mL) was added B2Pin2 (1131mg, 4.45 mmol, 1.5 equiv) and methyl isonicotinate (0.29 mL, 2.45 mmol,0.5 equiv). The resulting mixture was heated to 80° C. under anatmosphere of argon. After 4 hours, the reaction mixture was filtered,concentrated, and purified by SiO₂ chromatography (0-50% EtOAc/Hex),affording3-fluoro-6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)indazole.ES/MS m/z: 385.20 [M+H].

Intermediate 218.6-chloro-3-fluoro-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith4,4,5,5-tetramethyl-2-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]-1,3,2-dioxaborolane(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 356.10[M+H].

Intermediate 219.5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1-methyl-pyridin-2-one

5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1-methyl-pyridin-2-one(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith1-methyl-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridin-2-one(racemic mixture). ES/MS m/z: 301.10 [M+H].

Intermediate 220.6-chloro-8-[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 322.10[M+H].

Intermediate 221.6-chloro-3-fluoro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(Racemic Mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 289.10[M+H].

Intermediate 222.6-chloro-3-fluoro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith3-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(Racemic Mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 289.10[M+H].

Intermediate 223.6-chloro-3-fluoro-8-[(1S,2S)-2-pyrimidin-5-ylcyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-pyrimidin-5-ylcyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyrimidine(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z:290.10[M+1-1].

Intermediate 224.6-chloro-3-fluoro-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(Racemic Mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 289.10[M+H].

Intermediate 225. Ethyl6-chloro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylate

Ethyl6-chloro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylate(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine withethyl 8-bromo-6-chloroimidazo[1,2-b]pyridazine-2-carboxylate. ES/MS m/z:360.10 [M+H].

Intermediate 226.5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl]isoquinoline

5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]isoquinoline(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]isoquinoline(racemic mixture). ES/MS m/z: 321.10 [M+H].

Intermediate 227.4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl]quinoline

4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 321.10 [M+H].

Intermediate 228.8-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl]isoquinoline

8-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]isoquinoline(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith8-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]isoquinoline(racemic mixture). ES/MS m/z: 321.10 [M+H].

Intermediate 229.6-chloro-8-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(racemic mixture). ES/MS m/z: 356.10 [M+H].

Intermediate 230.6-chloro-8-[(1S,2S)-2-(5-fluoro-3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(5-fluoro-3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith3-fluoro-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(racemic mixture). ES/MS m/z: 289.10 [M+H].

Intermediate 231.6-chloro-8-[(1S,2S)-2-[6-(trifluoromethyl)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[6-(trifluoromethyl)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-2-(trifluoromethyl)pyridine(racemic mixture). ES/MS m/z: 339.00 [M+H].

Intermediate 232.3-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl]quinoline

3-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith3-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 321.10 [M+H].

Intermediate 233.6-chloro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith3-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine.ES/MS m/z: 271.10 [M+H].

Intermediate 234.6-chloro-8-[(1S,2S)-2-(3-fluoro-4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(3-fluoro-4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith3-fluoro-4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(racemic mixture). ES/MS m/z: 289.10 [M+H].

Intermediate 235.6-chloro-8-[(1S,2S)-2-[2-(trifluoromethyl)-4-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[2-(trifluoromethyl)-4-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith 3[(1S,2S)-2-[2-(trifluoromethyl)-4-pyridyl]cyclopropyl]boronic acid(racemic mixture). ES/MS m/z: 339.10 [M+H].

Intermediate 236.6-chloro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith6-chloro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 339.10 [M+H].

Intermediate 237.4-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]benzonitrile

4-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]benzonitrilewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile.ES/MS m/z: 313.10 [M+H].

Intermediate 238.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

8-bromo-6-chloro-imidazo[1,2-b]pyridazine (124 mg, 0.534 mmol),4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile(150 mg, 0.445 mmol), cataCXium A Pd G3 (32 mg, 0.0445 mmol), andpotassium phosphate tribasic (283 mg, 1.33 mmol) were weighed into amicrowave vial, which was then evacuated and refilled with N₂ 3 times.Pre-degassed dioxane (2.5 mL) and water (0.5 mL) were added, and thevial was sealed and heated to 110° C. for 3 h. The mixture was thenfiltered through celite, washing with EtOAc. The filtrate wasconcentrated in vacuo and purified by silica gel chromatography (0-100%EtOAc in hexanes) to afford4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile(racemic mixture). ES/MS m/z: 363.1 [M+H].

Intermediate 239.6-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]isoquinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]isoquinoline(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]isoquinoline(racemic mixture). ES/MS m/z: 321.10 [M+H].

Intermediate 240.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]pyridine-3-carbonitrile

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]pyridine-3-carbonitrile(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine-3-carbonitrile(racemic mixture). ES/MS m/z: 296.10 [M+H].

Intermediate 241.6-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl]quinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith7-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 321.10 [M+H].

Intermediate 242.6-chloro-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-5-(trifluoromethyl)pyridine(Racemic Mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 357.10[M+H].

Intermediate 243.6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]pyridine-3-carbonitrile

6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]pyridine-3-carbonitrile(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine-3-carbonitrile(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 314.10[M+H].

Intermediate 244.6-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 389.10 [M+H].

Intermediate 245.6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline

6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-8-(trifluoromethyl)quinolineand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 407.10[M+H].

Intermediate 246.6-chloro-8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-(difluoromethoxy)-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 355.10[M+H].

Intermediate 247.6-chloro-8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-(difluoromethoxy)-2-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]pyridine(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 355.10[M+H].

Intermediate 248.3-[(1R,2R)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline

3-[(1R,2R)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith3-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 389.10 [M+H].

Intermediate 249.7-[(1R,2R)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-5-(trifluoromethyl)quinoline

7-[(1R,2R)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-5-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith7-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-5-(trifluoromethyl)quinoline.ES/MS m/z: 389.10 [M+H].

Intermediate 250.6-chloro-2-cyclopropyl-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-2-cyclopropyl-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazine. ES/MS m/z:346.20 [M+H].

Intermediate 251.5-[(1S,2S)-2-(6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1,3-benzothiazole

5-[(1S,2S)-2-(6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1,3-benzothiazole(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1,3-benzothiazole(racemic mixture) and 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazine. ES/MS m/z:367.10 [M+H].

Intermediates 252 and 253.6-chloro-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazineand6-chloro-3-fluoro-8-[(1R,2R)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazineand6-chloro-3-fluoro-8-[(1R,2R)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazinewere chirally separated from the racemic mixture by SFC OJ-H column (10%EtOH).

Intermediate 254.6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one

6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-onewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith3,3-dimethyl-6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)indolin-2-oneand 8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z:453.10 [M+H].

Intermediate 255.6-chloro-3-fluoro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith3-fluoro-6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)indazoleand 8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z:428.110 [M+H].

Intermediate 256.6-chloro-8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-3-fluoro-imidazo[1,2-b]pyridazinewas prepared as follows: A microwave vial was charged with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine (200 mg, 0.799 mmol,1 equiv), (3S,4R)-3,4-difluoropyrrolidine hydrochloride (138 mg, 0.958mmol, 1.2 equiv), DIPEA (0.343 mL, 1.92 mmol, 2.4 equiv), and MeCN (5mL). The reaction mixture was heated to 85° C. After 24 hours, thereaction mixture was concentrated. The residue obtained was trituratedwith water, the resulting solids were filtered, washed with water, anddried affording6-chloro-8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 277.10.

Intermediate 257.6-chloro-8-(3,3-difluoropyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoropyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with3,3-difluoropyrrolidine. ES/MS m/z: 277.10.

Intermediate 258.6-chloro-8-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with(3R)-3-(trifluoromethyl)pyrrolidine; hydrochloride. ES/MS m/z: 291.10.

Intermediate 259.6-chloro-8-[(3S)-3-isopropylpyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[(3S)-3-isopropylpyrrolidin-1-yl]imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with(3S)-3-isopropylpyrrolidine; hydrochloride. ES/MS m/z: 265.20.

Intermediate 260.6-chloro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with7-fluoro-5-azaspiro[2.4]heptane; hydrochloride. ES/MS m/z: 267.10.

Intermediate 261.6-chloro-8-[7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with7-(difluoromethyl)-5-azaspiro[2.4]heptane; hydrochloride. ES/MS m/z:299.10.

Intermediate 262.6-chloro-8-[3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with3-fluoro-3-(trifluoromethyl)pyrrolidine; hydrochloride. ES/MS m/z:309.10.

Intermediate 263.6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with3,3-difluoro-4,4-dimethyl-pyrrolidine; hydrochloride. ES/MS m/z: 305.00.

Intermediate 264.6-chloro-3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with7-fluoro-5-azaspiro[2.4]heptane; hydrochloride. ES/MS m/z: 285.10.

Intermediate 265.6-chloro-7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidine

6-chloro-7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with7-fluoro-5-azaspiro[2.4]heptane; hydrochloride and5,7-dichloropyrazolo[1,5-a]pyrimidine. ES/MS m/z: 267.10.

Intermediate 266.6-chloro-2-cyclopropyl-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-2-cyclopropyl-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with3,3-difluoro-4,4-dimethyl-pyrrolidine; hydrochloride and8-bromo-6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazine. ES/MS m/z:327.10.

Intermediate 267.1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoro-pyrrolidin-3-ol

1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoro-pyrrolidin-3-olwas prepared in the manner described for Intermediate 256, but replacing(3S,4R)-3,4-difluoropyrrolidine hydrochloride with4,4-difluoropyrrolidin-3-ol; hydrochloride. ES/MS m/z: 275.10.

Intermediate 268.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 460.20 [M+H].

Intermediate 269.5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1-methyl-pyridin-2-one

5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1-methyl-pyridin-2-onewas prepared as a racemic mixture using5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1-methyl-pyridin-2-one(racemic mixture). ES/MS m/z: 405.20 [M+H].

Intermediate 270.8-[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 426.20 [M+H].

Intermediate 271.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 393.20 [M+H].

Intermediate 272.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 393.20 [M+H].

Intermediate 273.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-pyrimidin-5-ylcyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-pyrimidin-5-ylcyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-pyrimidin-5-ylcyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 394.20 [M+H].

Intermediate 274.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 393.20 [M+H].

Intermediate 275.8-[(3S,4R)-3,4-difluoropyrrolidin-1-0]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine

8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 381.20 [M+H].

Intermediate 276.8-(3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine

8-(3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoropyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 381.20 [M+H].

Intermediate 277.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 395.10 [M+H].

Intermediate 278.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(38)-3-isopropylpyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3S)-3-isopropylpyrrolidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(3S)-3-isopropylpyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 369.20 [M+H].

Intermediate 279.6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(4-methoxyphenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(4-methoxyphenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[3-(4-methoxyphenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 433.20 [M+H].

Intermediate 280.6-(2,4-dimethoxypyrimidin-5-yl)-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 371.20 [M+H].

Intermediate 281. Ethyl6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylate(Racemic Mixture)

Ethyl6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylate(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with ethyl6-chloro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylate(racemic mixture). ES/MS m/z: 464.20 [M+H].

Intermediate 282.8-[7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-[7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 403.10 [M+H].

Intermediate 283.6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 413.20 [M+H].

Intermediate 284.5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]isoquinoline(Racemic Mixture)

5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]isoquinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with (racemicmixture). ES/MS m/z: 425.20 [M+H].

Intermediate 285.4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(Racemic Mixture)

4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 425.20 [M+H].

Intermediate 286.5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(Racemic Mixture)

5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with (racemicmixture). ES/MS m/z: 425.20 [M+H].

Intermediate 287.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 460.20 [M+H].

Intermediate 288.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(5-fluoro-3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(5-fluoro-3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(5-fluoro-3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 393.20 [M+H].

Intermediate 289.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[6-(trifluoromethyl)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[6-(trifluoromethyl)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[6-(trifluoromethyl)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 443.10 [M+H].

Intermediate 290.3-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(Racemic Mixture)

3-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with3-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 425.20 [M+H].

Intermediate 291.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 393.20 [M+H].

Intermediate 292.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-fluoro-4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-fluoro-4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(3-fluoro-4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 393.20 [M+H].

Intermediate 293.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[2-(trifluoromethyl)-4-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[2-(trifluoromethyl)-4-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[2-(trifluoromethyl)-4-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 443.20 [M+H].

Intermediate 294.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 443.20 [M+H].

Intermediate 295.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 425.20 [M+H].

Intermediate 296.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]isoquinoline(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]isoquinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]isoquinoline(racemic mixture). ES/MS m/z: 425.20 [M+H].

Intermediate 297.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]pyridine-3-carbonitrile(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]pyridine-3-carbonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]pyridine-3-carbonitrile(racemic mixture). ES/MS m/z: 400.20 [M+H].

Intermediate 298.7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(Racemic Mixture)

7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 425.20 [M+H].

Intermediate 299.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]pyridine-3-carbonitrile(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]pyridine-3-carbonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]pyridine-3-carbonitrile(racemic mixture). ES/MS m/z: 418.10 [M+H].

Intermediate 300.8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine

8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 409.20 [M+H].

Intermediate 301.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 389.20 [M+H].

Intermediate 302.5-(2,4-dimethoxypyrimidin-5-yl)-7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidine

5-(2,4-dimethoxypyrimidin-5-yl)-7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 371.20 [M+H].

Intermediate 303.8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 441.20 [M+H].

Intermediate 304.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(trifluoromethyl)quinoline(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(trifluoromethyl)quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(trifluoromethyl)quinoline(racemic mixture). ES/MS m/z: 493.10 [M+H].

Intermediate 305.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline(racemic mixture). ES/MS m/z: 493.10 [M+H].

Intermediate 306.8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 441.20 [M+H].

Intermediate 307.7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-4-(trifluoromethyl)quinoline(Racemic Mixture)

7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-4-(trifluoromethyl)quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(trifluoromethyl)quinoline(racemic mixture). ES/MS m/z: 493.20 [M+H].

Intermediate 308.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-(trifluoromethyl)isoquinoline(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-(trifluoromethyl)isoquinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-(trifluoromethyl)isoquinoline(racemic mixture). ES/MS m/z: 493.20 [M+H].

Intermediate 309.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 493.10 [M+H].

Intermediate 310.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 511.20 [M+H].

Intermediate 311.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-(trifluoromethyl)isoquinoline

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-(trifluoromethyl)isoquinolinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-(trifluoromethyl)isoquinoline.ES/MS m/z: 493.20 [M+H].

Intermediate 312.8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol]-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 478.20 [M+H].

Intermediate 313.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(1-isopropylindazol-6-yl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(1-isopropylindazol-6-yl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-(1-isopropylindazol-6-yl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 456.20 [M+H].

Intermediate 314.8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 459.20 [M+H].

Intermediate 315.8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 459.20 [M+H].

Intermediate 316.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(trifluoromethyl)quinoline

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(trifluoromethyl)quinoline.ES/MS m/z: 493.10 [M+H].

Intermediate 317.8-1(1S,2S)-2-[1-(cyclopropylmethyl)indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[1-(cyclopropylmethyl)indazol]-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(cyclopropylmethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 468.20 [M+H].

Intermediate 318.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 496.20 [M+H].

Intermediate 319.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 496.20 [M+H].

Intermediate 320.8-[(1S,2S)-2-[3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 536.20 [M+H].

Intermediate 321.8-[(1S,2S)-2-[1-[(2,2-difluorocyclopropyl)methyl]indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[1-[(2,2-difluorocyclopropyl)methyl]indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-[(2,2-difluorocyclopropyl)methyl]indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 504.20 [M+H].

Intermediate 322.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 514.20 [M+H].

Intermediate 323.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 496.20 [M+H].

Intermediate 324.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-isopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-isopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[3-isopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 536.20 [M+H].

Intermediate 325.3-[(1R,2R)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline

3-[(1R,2R)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with3-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 493.10 [M+H].

Intermediate 326.7-[(1R,2R)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-(trifluoromethyl)quinoline

7-[(1R,2R)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-(trifluoromethyl)quinolinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-5-(trifluoromethyl)quinoline.ES/MS m/z: 493.10 [M+H].

Intermediate 327 and 328.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazineand6-(2,4-dimethoxypyrimidin-5-yl)-8-1(1R,2R)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazineand6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1R,2R)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazinewere chirally separated from the racemic mixture by SFC AD-H column (20%EtOH).

Intermediate 329.2-cyclopropyl-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

2-cyclopropyl-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-2-cyclopropyl-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 450.10 [M+H].

Intermediate 330.6-[(1S,2S)-2-[2-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1,3-benzothiazole(Racemic Mixture)

6-[(1S,2S)-2-[2-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1,3-benzothiazole(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloro-2-cyclopropyl-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1,3-benzothiazole(racemic mixture). ES/MS m/z: 450.10 [M+H].

Intermediate 331.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazineES/MS m/z: 461.20 [M+H].

Intermediate 332.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1R,2R)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1R,2R)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1R,2R)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazineES/MS m/z: 461.20 [M+H].

Intermediate 333.2-cyclopropyl-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

2-cyclopropyl-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-2-cyclopropyl-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 431.20 [M+H].

Intermediate 334.4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]benzonitrile

4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]benzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]benzonitrile.ES/MS m/z: 417.10 [M+H].

Intermediate 335.1-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-olwas

1-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-olwas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoro-pyrrolidin-3-ol.ES/MS m/z: 379.10 [M+H].

Intermediate 336.8-[(1S,2S)-2-[1-(2,2-difluoroethyl)-7-fluoro-indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(Racemic Mixture)

8-[(1S,2S)-2-[1-(2,2-difluoroethyl)-7-fluoro-indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(2,2-difluoroethyl)-7-fluoro-indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 496.20 [M+H].

Intermediate 337.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1R,2R)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1R,2R)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1R,2R)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture).

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1R,2R)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas chirally separated from the racemic mixture. ES/MS m/z: 514.20[M+H].

Intermediate 338.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-4-(2,2,2-trifluoroethoxy)isoquinoline(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-4-(2,2,2-trifluoroethoxy)isoquinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(2,2,2-trifluoroethoxy)isoquinoline(racemic mixture). ES/MS m/z: 523.20 [M+H].

Intermediate 339.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-4-(2,2,2-trifluoroethoxy)quinoline(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-4-(2,2,2-trifluoroethoxy)quinoline(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(2,2,2-trifluoroethoxy)quinoline(racemic mixture). ES/MS m/z: 523.20 [M+H].

Intermediate 340.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1-(2,2,2-trifluoroethyl)quinolin-4-one(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1-(2,2,2-trifluoroethyl)quinolin-4-one(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)quinolin-4-one(racemic mixture). ES/MS m/z: 523.20 [M+H].

Intermediate 341.7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(2,2,2-trifluoroethyl)isoquinolin-1-one(Racemic Mixture)

7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(2,2,2-trifluoroethyl)isoquinolin-1-one(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(2,2,2-trifluoroethyl)isoquinolin-1-one(racemic mixture). ES/MS m/z: 523.20 [M+H].

Intermediate 342.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 514.20 [M+H].

Intermediate 343.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 496.20 [M+H].

Intermediate 344.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one(racemic mixture).6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-onewas chirally separated from the racemic mixture by SFC IB column (10%IPA-NH₃). ES/MS m/z: 539.20 [M+H].

Intermediate 345.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture)

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 564.20 [M+H].

Intermediate 346.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one(racemic mixture). ES/MS m/z: 540.20 [M+H]./

Intermediate 347.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-onewas chirally separated from Intermediate 346 by SFC Cell 2 column (20%EtOH). ES/MS m/z: 540.20 [M+H].

Intermediate 348.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-one(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-one(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-one(racemic mixture). ES/MS m/z: 540.20 [M+H].

Intermediate 349.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-onewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloro-3-fluoro-imidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one.ES/MS m/z: 557.20 [M+H].

Intermediate 350.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b].ES/MS m/z: 532.20 [M+H].

Intermediate 351.6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas chirally separated from the racemic mixture by SFC AD-H column (15%ETOH). ES/MS m/z: 514.20 [M+H].

Intermediate 352.6-chloro-8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

A solution of racemic ((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)boronic acid(200 mg, 0.84 mmol, 1 equiv), 2-bromo-5-(difluoromethoxy)pyridine (226mg, 1.01 mmol, 1.2 equiv), potassium phosphate tribasic (536 mg, 2.53mmol, 3 equiv), and cataCXium-A-Pd-G3 (61 mg, 10 mol %) in 1:5water:1,4-dioxane (2.5 mL) was degassed with Argon for one minute andheated to 100° C. After 1 hour, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording racemic6-chloro-8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 337.00 [M+H].

Intermediate 353.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(trifluoromethyl)quinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(trifluoromethyl)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-2-(trifluoromethyl)quinoline. ES/MS m/z: 389.10 [M+H].

Intermediate 354.6-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(trifluoromethyl)quinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(trifluoromethyl)quinolinewas chirally separated from the racemic Intermediate 353 by SFC OJ-Hcolumn (35% EtOH).

Intermediate 355.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-8-(trifluoromethyl)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-8-(trifluoromethyl)quinoline. ES/MS m/z: 389.10 [M+H].

Intermediate 356.6-chloro-8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with5-bromo-2-(difluoromethoxy)pyridine. ES/MS m/z: 337.10 [M+H].

Intermediate 357.7-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(trifluoromethyl)quinolin

7-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(trifluoromethyl)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with7-bromo-4-(trifluoromethyl)quinoline. ES/MS m/z: 389.10 [M+H].

Intermediate 358.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-(trifluoromethyl)isoquinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-(trifluoromethyl)isoquinolinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3-(trifluoromethyl)isoquinoline. ES/MS m/z: 389.10 [M+H].

Intermediate 359.6-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-(trifluoromethyl)isoquinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-(trifluoromethyl)isoquinolinewas chirally separated from the racemic Intermediate 358 by SFC AD-Hcolumn (35% MeOH).

Intermediate 360.6-chloro-8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol]-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2-difluoroethyl)indazole. ES/MS m/z: 374.10 [M+H]. and

Intermediate 361.6-chloro-8-[(1S,2S)-2-(1-isopropylindazol-6-yl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(1-isopropylindazol-6-yl)cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-isopropyl-indazole. ES/MS m/z: 352.20 [M+H].

Intermediate 362.6-chloro-8-[(1S,2S)-2-[1-(cyclopropylmethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(cyclopropylmethyl)indazol]-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(cyclopropylmethyl)indazole. ES/MS m/z: 364.20 [M+H].

Intermediate 363.6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridine. ES/MS m/z:392.10 [M+H].

Intermediate 364.6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridine. ES/MS m/z:392.10 [M+H].

Intermediate 365.6-chloro-8-[(1S,2S)-2-[3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazole. ES/MS m/z:432.10 [M+H].

Intermediate 366.6-chloro-8-[(1S,2S)-2-[1-[(2,2-difluorocyclopropyl)methyl]indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-[(2,2-difluorocyclopropyl)methyl]indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-[(2,2-difluorocyclopropyl)methyl]indazole. ES/MS m/z: 400.10[M+1-1].

Intermediate 367.6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridine. ES/MSm/z: 410.10 [M+H].

Intermediate 368.6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas chirally separated from the racemic Intermediate 367 by SFC AD-Hcolumn (20% IPA-NH₃). ES/MS m/z: 410.10 [M+H].

Intermediate 369.6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridine.

Single enantiomer6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas chirally separated from the racemic by SFC AD-H column (20%IPA-NH₃). ES/MS m/z: 392.10 [M+H].

Intermediate 370.6-chloro-8-[(1S,2S)-2-[3-isopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[3-isopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3-isopropyl-1-(2,2,2-trifluoroethyl)indazole. ES/MS m/z: 434.10[M+H].

Intermediate 371.6-chloro-8-[(1S,2S)-2-[1-(2,2-difluoroethyl)-7-fluoro-indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2-difluoroethyl)-7-fluoro-indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2-difluoroethyl)-7-fluoro-indazole. ES/MS m/z: 392.10[M+H].

Intermediate 372.6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)indazole. ES/MS m/z: 410.10[M+H]. and

Intermediate 373.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(2,2,2-trifluoroethoxy)isoquinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(2,2,2-trifluoroethoxy)isoquinolinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-4-(2,2,2-trifluoroethoxy)isoquinoline andR1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]boronicacid. ES/MS m/z: 419.10 [M+H].

Intermediate 374.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(2,2,2-trifluoroethoxy)quinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-4-(2,2,2-trifluoroethoxy)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-4-(2,2,2-trifluoroethoxy)quinoline. ES/MS m/z: 419.10 [M+H].

Intermediate 375.6-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)quinolin-4-one

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-1-(2,2,2-trifluoroethyl)quinolin-4-onewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2,2-trifluoroethyl)quinolin-4-one. ES/MS m/z: 419.10 [M+H].

Intermediate 376.7-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(2,2,2-trifluoroethyl)isoquinolin-1-one

7-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-(2,2,2-trifluoroethyl)isoquinolin-1-onewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with7-bromo-2-(2,2,2-trifluoroethyl)isoquinolin-1-one. ES/MS m/z: 419.10[M+H].

Intermediate 377.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-onewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one. ES/MS m/z:435.10 [M+H].

Intermediate 378.6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridine. ES/MS m/z:392.10 [M+H].

Intermediate 379.6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas chirally separated from the racemic Intermediate 378 by SFC IBcolumn (5% EtOH). ES/MS m/z: 392.10 [M+H].

Intermediate 380.6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridine.ES/MS m/z: 460.20 [M+H].

Intermediate 381.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-onewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one.ES/MS m/z: 436.40 [M+H].

Intermediate 382.6-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-one

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-onewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-chloro-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-2-one.ES/MS m/z: 436.40 [M+H].

Intermediate 383.5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: A solution of5,7-dichloropyrazolo[1,5-a]pyrimidine (200 mg, 1.06 mmol, 1 equiv),3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride (201 mg, 1.17 mmol,1.1 equiv) and potassium carbonate (296 mg, 2.13 mmol, 2 equiv) in EtOH(1.6 mL) was heated to 85° C. and stirred for 1 h. The reaction mixturewas diluted with water and extracted with EtOAc (3×). The organic layerswere combined, washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound. ES/MS m/z: 287.0[M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, J=2.3 Hz, 1H), 6.41 (d,J=2.3 Hz, 1H), 6.07 (s, 1H), 4.52 (t, J=13.7 Hz, 2H), 3.98 (s, 2H), 1.19(s, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.43.

Intermediate 384.5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-ethylpyrazolo[1,5-a]pyrimidine

5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-ethylpyrazolo[1,5-a]pyrimidinewas prepared as follows: To a solution of5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (155 mg, 0.717 mmol, 1equiv) and 3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride (135 mg,0.789 mmol, 1.1 equiv) in ACN (4.0 mL) was added DIPEA (0.30 mL, 1.72mmol, 2.4 equiv). The solution was heated to 85° C. and stirred for 3 hand 20 min. The reaction mixture was diluted with water, the resultingsolids filtered, washed with water and dried to afford the titlecompound. ES/MS m/z: 315.1 [M+H]. ¹H NMR (400 MHz, Chloroform-d) δ 7.81(s, 1H), 5.64 (s, 1H), 4.51 (t, J=13.4 Hz, 2H), 3.77 (s, 2H), 2.74 (q,J=7.6 Hz, 2H), 1.29-1.21 (m, 9H). ¹⁹F NMR (376 MHz, Chloroform-d) δ−116.66.

Intermediate 385.3,5-dichloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-3/1)pyrazolo[1,5-a]pyrimidine

3,5-dichloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: A solution of3,5,7-trichloropyrazolo[1,5-a]pyrimidine (200 mg, 0.899 mmol, 1 equiv),DIPEA (0.17 mL, 0.989 mmol, 1.1 equiv) and7,7-difluoro-5-azaspiro[2.4]heptane (132 mg, 0.989 mmol, 1.1 equiv) inACN (4.0 mL) was stirred at room temperature for 2 h and 40 min prior todilution with water, filtering the resulting solids, washing furtherwith water and drying to afford the title compound. ES/MS m/z: 319.0[M+H. ¹H NMR (400 MHz, Chloroform-d) δ 7.89 (s, 1H), 5.72 (s, 1H), 4.58(t, J=12.1 Hz, 2H), 4.06 (s, 2H), 1.25-1.18 (m, 2H), 0.92-0.85 (m, 2H).¹⁹F NMR (376 MHz, Chloroform-d) δ −110.06.

Intermediates 386 and 387.5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidineand3,5-dichloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-3/1)pyrazolo[1,5-a]pyrimidine

5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidineand3,5-dichloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidinewere prepared in the manner described for Intermediate 385, butreplacing 3,5,7-trichloropyrazolo[1,5-a]pyrimidine with a mixture of5,7-dichloro-3-fluoropyrazolo[1,5-a]pyrimidine and3,5,7-trichloropyrazolo[1,5-a]pyrimidine and7,7-difluoro-5-azaspiro[2.4]heptane with3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride. The reaction mixturewas stirred at room temperature for 4 h and 20 min prior to dilutionwith water, filtering the resulting solids, washing with water anddrying to afford the title compounds as a mixture.

Intermediate 386:5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidineES/MS m/z: 305.0 [M+H].

Intermediate 387:3,5-dichloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidineES/MS m/z: 321.0 [M+H].

Intermediate 388.5-chloro-7-(3,3-difluoro-4-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

5-chloro-7-(3,3-difluoro-4-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: A solution of5,7-dichloropyrazolo[1,5-a]pyrimidine (200 mg, 1.06 mmol, 1 equiv),3,3-difluoro-4-methylpyrrolidine hydrochloride (184 mg, 1.17 mmol, 1.1equiv) and DIPEA (0.44 mL, 2.55 mmol, 2.4 equiv) in ACN (4.0 mL) washeated to 85° C. and stirred overnight prior to dilution with water,filtering the resulting solids, washing with water and drying to affordthe title compound. ES/MS m/z: 273.0 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ8.10 (d, J=2.2 Hz, 1H), 6.41 (d, J=2.2 Hz, 1H), 6.08 (s, 1H), 4.54-4.42(m, 2H), 4.42-4.31 (m, 1H), 3.74-3.63 (m, 1H), 2.92-2.73 (m, 1H), 1.13(d, J=6.8 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −110.05 (d, J=227.9 Hz),−113.87 (d, J=227.8 Hz).

Intermediate 389.5-chloro-7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidine

5-chloro-7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 385, but replacing3,5,7-trichloropyrazolo[1,5-a]pyrimidine with5,7-dichloro-3-fluoropyrazolo[1,5-a]pyrimidine and7,7-difluoro-5-azaspiro[2.4]heptane with3,3-difluoro-4-methylpyrrolidine hydrochloride. The solution was stirredat room temperature for 4 h and 30 min. The reaction mixture was dilutedwith water and the resulting solids filtered. The solids were dissolvedin EtOAc and the filtrate was concentrated in vacuo to afford the titlecompound. ES/MS m/z: 291.0 [M+H].

Intermediate 390:5-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1H-imidazo[4,5-b]pyridine

5-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-1H-imidazo[4,5-b]pyridinewas prepared as follows: To a solution of5,7-dichloro-1H-imidazo[4,5-b]pyridine (400 mg, 2.13 mmol, 1 equiv) and7,7-difluoro-5-azaspiro[2.4]heptane (340 mg, 2.55 mmol, 1.2 equiv) inACN (10.0 mL) was added DIPEA (0.74 mL, 4.25 mmol, 2 equiv). Thesolution was heated to 140° C. and stirred overnight. Additional7,7-difluoro-5-azaspiro[2.4]heptane (340 mg, 2.55 mmol, 1.2 equiv) wasadded and the reaction mixture was stirred at 140° C. for 3 days. Thesolution was diluted with water and the resulting solids filtered. Thefiltrate was re-filtered and the two filter cakes were combined anddried to afford the title compound. ES/MS m/z: 285.1 [M+H]. ¹H NMR (400MHz, DMSO-d₆) δ 12.91 (s, 1H), 8.11 (s, 1H), 6.25 (s, 1H), 4.40 (t,J=12.7 Hz, 2H), 3.99 (s, 2H), 1.07-1.01 (m, 2H), 0.97-0.92 (m, 2H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −107.25.

Intermediate 391.5-bromo-7-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine

5-bromo-7-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: A microwave vial was charged with potassium((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)trifluoroborate (99 mg,0.361 mmol, 1 equiv), 5,7-dibromopyrazolo[1,5-a]pyrimidine (110 mg,0.397 mmol, 1.1 equiv), palladium-tetrakis(triphenylphosphine) (21 mg,0.018 mmol, 0.05 equiv) and cesium carbonate (353 mg, 1.08 mmol, 3equiv). To this was added toluene (3.0 mL) and water (0.60 mL). Thereaction mixture was heated to 90° C. and stirred for 2 h and 15 minbefore turning off the heat and letting the solution stir. The solutionwas heated again to 90° C. and stirred for 4 h and 15 min before turningoff the heat again and leaving to stir overnight. The reaction mixturewas diluted with EtOAc and filtered through a pad of Celite. Thefiltrate was diluted with water and the aqueous layer was extracted withEtOAc (2×). The organic fractions were combined, dried over MgSO₄,filtered and concentrated in vacuo prior to purification by silica gelchromatography (0-30% EtOAc in hexanes) to afford the title compound.ES/MS m/z: 363.9 [M+H]. ¹H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J=2.3Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 6.81-6.42 (m,3H), 3.17-3.06 (m, 1H), 2.73-2.60 (m, 1H), 1.92-1.74 (m, 2H). ¹⁹F NMR(376 MHz, Chloroform-d) δ −110.88.

Intermediate 392.7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine

7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: A microwave vial was charged with5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine(150 mg, 0.523 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(130 mg, 0.707 mmol, 1.35 equiv), Pd(dppf)Cl₂·CH₂Cl₂ (43 mg, 0.052 mmol,0.1 equiv) and cesium carbonate (511 mg, 1.57 mmol, 3 equiv). To thiswas added 1,4 dioxane (2.0 mL) and water (0.40 mL). The reaction mixturewas heated to 90° C. and stirred overnight. After cooling to roomtemperature, the mixture was diluted with EtOAc and filtered through apad of Celite. The filtrate was concentrated under reduced pressure andthe crude material was purified by silica gel chromatography (0-100%EtOAc in hexanes) to afford the title compound. ES/MS m/z: 391.1 [M+H].¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.09 (d, J=2.3 Hz, 1H),6.50-6.46 (m, 2H), 4.55 (t, J=13.8 Hz, 2H), 4.05 (s, 3H), 3.98 (s, 3H),3.95 (s, 2H), 1.22 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.16.

Intermediate 393.7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-ethylpyrazolo[1,5-a]pyramidine

7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-ethylpyrazolo[1,5-a]pyrimidinewas prepared as follows: A microwave vial was charged with5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-ethylpyrazolo[1,5-a]pyrimidine(150 mg, mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (139mg, 0.756 mmol, 1.59 equiv), Pd(dppf)Cl₂CH₂Cl₂ (39 mg, 0.048 mmol, 0.1equiv) and cesium carbonate (311 mg, mmol, 2 equiv). To this was added1,4 dioxane (2.0 mL) and water (0.40 mL). The reaction mixture washeated to 90° C. and stirred overnight. After cooling to roomtemperature, the mixture was diluted with EtOAc and filtered through apad of Celite. The filtrate was concentrated under reduced pressure andthe crude material was purified by silica gel chromatography (0-100%EtOAc in hexanes) to afford the title compound. ES/MS m/z: 419.0 [M+H].¹H NMR (400 MHz, Chloroform-d) δ 8.99 (s, 1H), 7.84 (s, 1H), 6.26 (s,1H), 4.62-4.45 (m, 2H), 4.16-4.04 (m, 6H), 3.84 (s, 2H), 2.88-2.75 (m,2H), 1.37-1.25 (m, 9H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −116.32.

Intermediate 394.3-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine

3-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: A microwave vial was charged with(2,4-dimethoxypyrimidin-5-yl)boronic acid (140 mg, 0.762 mmol, 1.3equiv),3,5-dichloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidine(187 mg, 0.586 mmol, 1 equiv), Pd(dppf)Cl₂CH₂Cl₂ (48 mg, 0.059 mmol, 0.1equiv) and cesium carbonate (572 mg, 1.76 mmol, 3 equiv). To this wasadded 1,4 dioxane (2.0 mL) and water (0.40 mL). The reaction mixture washeated to 90° C. and stirred overnight. After cooling to roomtemperature, the mixture was diluted with EtOAc and filtered through apad of Celite. The filtrate was concentrated under reduced pressure andthe crude material was purified by silica gel chromatography (0-100%EtOAc in hexanes) to afford the title compound. ES/MS m/z: 423.0 [M+H].¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.26 (s, 1H), 6.59 (s, 1H),4.63 (t, J=12.4 Hz, 2H), 4.16 (s, 2H), 4.06 (s, 3H), 3.99 (s, 3H),1.10-0.98 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −107.57.

Intermediates 395 and 396.7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-fluoropyrazolo[1,5-a]pyrimidineand3-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine

7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-fluoropyrazolo[1,5-a]pyrimidineand3-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewere prepared in the manner described for Intermediate 394, butreplacing3,5-dichloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidinewith a mixture of5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidineand3,5-dichloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine.

Intermediate 395:7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-fluoropyrazolo[1,5-a]pyrimidineES/MS m/z: 409.1 [M-FH].

Intermediate 396:3-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidineES/MS m/z: 425.0 [M-FH].

Intermediate 397.7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine

7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: A microwave vial was charged with(2,4-dimethoxypyrimidin-5-yl)boronic acid (219 mg, 1.19 mmol, 1.35equiv),5-chloro-7-(3,3-difluoro-4-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine(240 mg, 0.880 mmol, 1 equiv), Pd(dppf)Cl₂CH₂Cl₂ (72 mg, 0.088 mmol, 0.1equiv) and cesium carbonate (860 mg, 2.64 mmol, 3 equiv). To this wasadded 1,4 dioxane (4.0 mL) and water (0.80 mL). The reaction mixture washeated to 90° C. and stirred for 6 h and 30 min. After cooling to roomtemperature, the mixture was diluted with EtOAc and filtered through apad of Celite. The filtrate was concentrated under reduced pressure andthe crude material was purified by silica gel chromatography (0-100%EtOAc in hexanes) to afford the title compound. ES/MS m/z: 377.1 [M+H].¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.09 (d, J=2.3 Hz, 1H), 6.49(s, 1H), 6.48 (d, J=2.3 Hz, 1H), 4.59-4.44 (m, 2H), 4.37-4.29 (m, 1H),4.04 (s, 3H), 3.98 (s, 3H), 3.71-3.63 (m, 1H), 2.95-2.77 (m, 1H), 1.16(d, J=6.8 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −109.34 (d, J=227.4 Hz),−113.60 (d, J=227.4 Hz).

Intermediate 398.7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-fluoropyrazolo[1,5-a]pyrimidine

7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-fluoropyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 397, but replacing5-chloro-7-(3,3-difluoro-4-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidinewith5-chloro-7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidine.ES/MS m/z: 395.1 [M+H].

Intermediates 399 and 400 5,7-dichloro-3-fluoropyrazolo[1,5-a]pyrimidineand 3,5,7-trichloropyrazolo[1,5-a]pyrimidine

5,7-dichloro-3-fluoropyrazolo[1,5-a]pyrimidine and3,5,7-trichloropyrazolo[1,5-a]pyrimidine were prepared as follows: To asolution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (500 mg, 2.66 mmol, 1equiv) in ACN (12.0 mL) was added Selectfluor™ (942 mg, 2.66 mmol, 1equiv). The reaction mixture was heated to 60° C. and stirred overnight.The reaction was then stirred at 70° C. for 1 h and 45 min. AdditionalSelectfluor™ (300 mg, 0.847 mmol) was added and the solution was stirredat 70° C. for 3 days. Additional Selectfluor™ (300 mg, 0.847 mmol) wasagain added and the reaction was stirred at 70° C. for 1 h and 30minutes. After cooling to room temperature, the reaction mixture wasquenched carefully with saturated sodium bicarbonate until gas formationceased. The solution was diluted with water and extracted with EtOAc(3×). The organic fractions were combined, dried over MgSO₄, filteredand concentrated in vacuo. The crude material was purified by silica gelchromatography (0-80% DCM in hexanes) to afford the title compounds as amixture. 3,5,7-trichloropyrazolo[1,5-a]pyrimidine was carried throughthe proceeding reactions as a side-product.

Intermediate 399 5,7-dichloro-3-fluoropyrazolo[1,5-a]pyrimidine ES/MSm/z: 206.0 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (d, J=3.3 Hz, 1H),7.71 (s, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −180.70.

Intermediate 400 3,5,7-trichloropyrazolo[1,5-a]pyrimidine ES/MS m/z:221.9 [M+H].

Intermediate 401 5,7-dibromopyrazolo[1,5-a]pyrimidine

5,7-dibromopyrazolo[1,5-a]pyrimidine was prepared as follows: A solutionof 5,7-dichloropyrazolo[1,5-a]pyrimidine (200 mg, 1.06 mmol, 1 equiv)and bromotrimethylsilane (0.70 mL, 5.32 mmol, 5 equiv) in ACN (5.0 mL)was stirred at room temperature for 2 h and 40 min. The reaction mixturewas heated to 50° C. and stirred for 1 h. It was then heated to 120° C.and stirred for an additional 1 h. The reaction mixture was loaded ontoCelite and purified by silica gel chromatography (0-10% MeOH in DCM) toafford the title compound. ES/MS m/z: 275.8 [M+H]. ¹H NMR (400 MHz,Chloroform-d) δ 8.21 (d, J=2.4 Hz, 1H), 7.28 (s, 1H), 6.79 (d, J=2.3 Hz,1H).

Intermediate 402. Potassium((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)trifluoroborate

Potassium((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)trifluoroborate wasprepared as follows: To a solution of2-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(169 mg, 0.575 mmol, 1 equiv) in 5:1 MeOH/H₂O (3.0 mL) was addedpotassium bifluoride (314 mg, 4.02 mmol, 7 equiv). The solution wasstirred at room temperature for 4 h prior to concentrating in vacuo. Themixture was diluted with ACN and filtered. The filtrate was concentratedin vacuo and the resulting solids were washed with Et2O, filtered anddried to afford the title compound. ¹H NMR (400 MHz, Acetonitrile-d3) δ7.34 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 6.69 (t, J=56.6 Hz, 1H),1.64-1.57 (m, 1H), 0.83-0.74 (m, 1H), 0.59-0.50 (m, 1H), −0.05-−0.16 (m,1H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −109.92, −143.89, −145.90 (m).

Intermediate 403. 4,4-difluoropyrrolidin-3-ol Hydrochloride

4,4-difluoropyrrolidin-3-ol hydrochloride was prepared as follows: To asolution of tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylatein DCM (5.0 mL) was added 4.0 M HCl in dioxane (5.0 mL, 20.2 mmol, 9equiv). The reaction mixture was stirred at room temperature. Uponcompletion, the solution was concentrated in vacuo to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 2H), 6.60 (d, J=4.8 Hz,1H), 4.36-4.27 (m, 1H), 3.72-3.51 (m, 2H), 3.50-3.42 (m, 1H), 3.26-3.19(m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −106.59 (d, J=237.6 Hz), −121.44(d, J=237.6 Hz).

Intermediate 404.1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol

1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol wasprepared as follows: A solution of8-bromo-6-chloroimidazo[1,2-b]pyridazine (523 mg, 2.25 mmol, 1 equiv),4,4-difluoropyrrolidin-3-ol hydrochloride (359 mg, 2.25 mmol, 1 equiv)and DIPEA (0.94 mL, 5.40 mmol, 2.4 equiv) in ACN (10.0 mL) was stirredat 70° C. for 1 h and 30 min. The heat was turned off and the reactionwas left to stir for 3 days. The reaction was heated to ° C. and stirredfor an additional 2 h and 30 min prior to cooling to room temperature,diluting with water and extracting the aqueous layer with EtOAc (2×).The organic fractions were combined, dried over MgSO₄, filtered andconcentrated in vacuo to afford the title compound. ES/MS m/z: 275.0[M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 8.09-8.06 (m, 1H), 7.60-7.58 (m, 1H),6.27 (d, J=5.2 Hz, 1H), 6.13 (s, 1H), 4.55-3.90 (m, 5H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −108.31-−111.78 (m), −122.76 (d, J=233.4 Hz).

Intermediate 405.1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol

1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwas prepared as follows: A microwave vial was charged with1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(650 mg, 2.37 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(653 mg, 3.55 mmol, 1.5 equiv), SPhos Pd G3 (277 mg, 0.355 mmol, 0.15equiv) and potassium carbonate (654 mg, 4.73 mmol, 2 equiv). To this wasadded 1,4 dioxane (10.0 mL) and water (1.0 mL). The reaction mixture washeated to 90° C. and stirred overnight. After cooling to roomtemperature, the solution was diluted with water and extracted withEtOAc (3×). The organic fractions were combined, dried over MgSO₄,filtered and concentrated in vacuo. The crude material was purified bysilica gel chromatography (0-100% EtOAc in hexanes then 0-30% MeOH inEtOAc) to afford the title compound. ES/MS m/z: 379.1 [M+H]. ¹H NMR (400MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.12 (d, J=1.2 Hz, 1H), 7.59 (d, J=1.2 Hz,1H), 6.28-6.23 (m, 2H), 4.53-4.06 (m, 5H), 4.00-3.96 (m, 6H). ¹⁹F NMR(376 MHz, DMSO-d₆) δ −109.26-−110.86 (m), −122.68 (d, J=232.8 Hz).

Intermediate 406.4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-3/1)oxy)benzonitrile

4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)benzonitrilewas prepared as follows: A solution of1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(50 mg, mmol, 1 equiv), 4-fluorobenzonitrile (32 mg, 0.264 mmol, 2equiv) and cesium carbonate (129 mg, 0.396 mmol, 3 equiv) in NMP (1.0mL) was heated to 85° C. and stirred for 2 h. The reaction mixture wasdiluted with a solution of saturated sodium bicarbonate and water. Theaqueous layer was extracted with EtOAc. The organic fractions werecombined, dried over MgSO₄, filtered and concentrated in vacuo prior topurification by silica gel chromatography (0-100% EtOAc in hexanes) toafford the title compound. ES/MS m/z: 480.1 [M+H].

Intermediate 407.8-(4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as follows: A solution of1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(30 mg, 0.079 mmol, 1 equiv), 2-chloro-5-(difluoromethyl)pyridine (26mg, 0.159 mmol, 2 equiv) and cesium carbonate (78 mg, 0.238 mmol, 3equiv) in NMP (1.0 mL) was heated to 85° C. and stirred for 45 min. Thetemperature was increased to 110° C. and the solution was left to stirfor 3 days. The reaction mixture was diluted with a saturated solutionof sodium bicarbonate and water. The aqueous layer was extracted withEtOAc. The organic fractions were combined, dried over MgSO₄ andconcentrated in vacuo prior to purification by silica gel chromatography(0-100% EtOAc in hexanes) to afford the title compound. ES/MS m/z: 506.1[M+H].

Intermediate 408.1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluorophenyl)carbamate

1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluorophenyl)carbamate was prepared as follows: To a solution of1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(60 mg, 0.159 mmol, 1 equiv) in THF (2.0 mL) in an ice bath wasgradually added NaH (60% dispersion in mineral oil) (19 mg, 0.476 mmol,3 equiv). 1-fluoro-2-isocyanatobenzene (0.04 mL, 0.317 mmol, 2 equiv)was subsequently added. The reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was quenched with water andthe aqueous layer was extracted with EtOAc (2×). The organic fractionswere combined, dried over MgSO₄, filtered and concentrated in vacuoprior to purification by silica gel chromatography (0-100% EtOAc inhexanes) to afford the title compound. ES/MS m/z: 516.1 [M+H].

Intermediate 409.3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2-fluorophenyl)carbamate

3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2-fluorophenyl)carbamate was prepared as follows: To a solution of3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol(66 mg, 0.15 mmol, 1 equiv) in DCM (2.0 mL) was added DIPEA (0.25 mL,1.5 mmol, 10 equiv), followed by 1-fluoro-2-isocyanatobenzene (0.16 mL,1.5 mmol, 10 equiv). The reaction mixture was heated to 60° C. andstirred for 1 h and 50 min. The temperature was increased to ° C. andthe solution was stirred overnight. The solution was diluted with waterand extracted with EtOAc (2×). Organic fractions were combined, driedover NaSO4, filtered and concentrated prior to purification by silicagel chromatography (0-100% EtOAc in hexanes) to afford the titlecompound. ES/MS m/z: 589.1 [M+H].

Intermediate 410.(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4-difluorophenyl)carbamate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4-difluorophenyl)carbamate was prepared as follows: To a solution of(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(42 mg, 0.091 mmol, 1 equiv) in DCM (0.75 mL) was added DIPEA (0.08 mL,0.454 mmol, 5 equiv). 4-nitrophenyl chloroformate (52 mg, 0.258 mmol,2.84 equiv) was subsequently added. The solution was stirred at roomtemperature for 50 min. 2,4-difluoroaniline (0.02 mL, 0.182 mmol, 2equiv) was then added and the solution was left to stir overnight. Thereaction mixture was treated with a saturated solution of sodiumbicarbonate and water and extracted with DCM. Organic fractions werecombined, dried over MgSO₄, filtered and concentrated prior topurification by silica gel chromatography (0-100% EtOAc in hexanes) toafford the title compound. ES/MS m/z: 506.0 [M+H].

Intermediate 411.(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluoro-4-methylphenyl)carbamate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluoro-4-methylphenyl)carbamate was prepared as follows: To asolution of(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(46 mg, 0.100 mmol, 1 equiv) in DCM (0.83 mL) was added DIPEA (0.17 mL,0.995 mmol, 10 equiv). 4-nitrophenyl chloroformate (46 mg, 0.228 mmol,2.29 equiv) was subsequently added. The solution was stirred at roomtemperature for 45 min. 2-fluoro-4-methylaniline (0.02 mL, 0.199 mmol, 2equiv) was then added and the solution was left to stir overnight. Thereaction mixture was treated with a saturated solution of sodiumbicarbonate and water and extracted with DCM (2×). Organic fractionswere combined, dried over MgSO₄ and concentrated prior to purificationby silica gel chromatography (0-100% EtOAc in hexanes) to afford thetitle compound. ES/MS m/z: 502.0 [M+H].

Intermediate 412.3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,4-difluorophenyl)carbamate

3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,4-difluorophenyl)carbamate was prepared as follows: To a solution of3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol(66 mg, 0.15 mmol, 1 equiv) in DCM (2.0 mL) was added DIPEA (0.25 mL,1.5 mmol, 10 equiv), followed by 2,4-difluoro-1-isocyanatobenzene (0.17mL, 1.5 mmol, 10 equiv). The reaction mixture was heated to 70° C. andstirred for 3 h and 20 min. The solution was diluted with water andextracted with EtOAc (2×). Organic fractions were combined, dried overNaSO4, filtered and concentrated prior to purification by silica gelchromatography (0-100% EtOAc in hexanes) to afford the title compound.ES/MS m/z: 607.1 [M+H].

Intermediate 413.(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4,6-trifluorophenyl)carbamate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4,6-trifluorophenyl)carbamate was prepared as follows: To a solutionof(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(32 mg, 0.069 mmol, 1 equiv) in DCM (2.0 mL) was added DIPEA (0.12 mL,0.69 mmol, 10 equiv), followed by 1,3,5-trifluoro-2-isocyanatobenzene(0.05 mL, 0.35 mmol, 5 equiv). The reaction mixture was heated to 60° C.and stirred for 4 h. The solution was diluted with water and extractedwith EtOAc (2×). Organic fractions were combined, dried over NaSO4,filtered and concentrated prior to purification by silica gelchromatography (0-100% EtOAc in hexanes) to afford the title compound.ES/MS m/z: 524.0 [M+H].

Intermediate 414.6-chloro-8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 10, but replacingpyrrolidine with 3-(4-fluorophenyl)azetidine hydrochloride. ES/MS m/z:303.1 [M+H].

Intermediate 415.6-chloro-8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 10, but replacingpyrrolidine with 3-fluoro-3-phenylazetidine hydrochloride. ES/MS m/z:303.0 [M+H].

Intermediate 416.6-chloro-8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 10, but replacingpyrrolidine with 4,4-difluoro-6-azaspiro[2.5]octane hydrochloride. ES/MSm/z: 299.0 [M+H].

Intermediate 417. Methyl4-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate

Methyl 4-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewas prepared in the manner described for Intermediate 10, but replacingpyrrolidine with methyl 4-(azetidin-3-yl)benzoate hydrochloride. ES/MSm/z: 343.1 [M+H].

Intermediate 418.6-chloro-3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 10, but replacing8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine, and pyrrolidine with3-(4-(trifluoromethyl)phenyl)pyrrolidine. ES/MS m/z: 385.1 [M+H].

Intermediate 419. Methyl3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate

Methyl 3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewas prepared in the manner described for Intermediate 10, but replacingpyrrolidine with methyl 3-(azetidin-3-yl)benzoate hydrochloride. ES/MSm/z: 343.1 [M+H].

Intermediate 420. Methyl3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate

Methyl3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate wasprepared in the manner described for Intermediate 10, but replacingpyrrolidine with methyl 3-(pyrrolidin-3-yl)benzoate hydrochloride. ES/MSm/z: 357.1 [M+H].

Intermediate 421. Methyl4-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate

Methyl4-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate wasprepared in the manner described for Intermediate 10, but replacingpyrrolidine with methyl 4-(pyrrolidin-3-yl)benzoate hydrochloride. ES/MSm/z: 357.1 [M+H].

Intermediate 422.6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine

6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[4,3-b]pyridazinewas prepared in the manner described for Intermediate 10, but replacing8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-[1,2,4]triazolo[4,3-b]pyridazine, and pyrrolidine with7,7-difluoro-5-azaspiro[2.4]heptane hydrochloride. ES/MS m/z: 286.0[M+H].

Intermediate 423.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-chloro-8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 407.2 [M+H].

Intermediate 424.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-chloro-8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 407.1 [M+H].

Intermediate 425.8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-chloro-8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 403.1 [M+H].

Intermediate 426. Methyl4-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate

Methyl4-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl4-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate. ES/MSm/z: 447.2 [M+H].

Intermediate 427.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-chloro-3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 489.2 [M+H].

Intermediate 428. Methyl3-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate

Methyl3-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate. ES/MSm/z: 447.2 [M+H].

Intermediate 429. Methyl3-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate

Methyl3-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoatewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl3-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate.ES/MS m/z: 461.2 [M+H].

Intermediate 430. Methyl4-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate

Methyl4-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoatewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl4-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate.ES/MS m/z: 461.2 [M+H].

Intermediate 431.8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine

8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[4,3-b]pyridazine.ES/MS m/z: 390.2 [M+H].

Intermediate 432.6-chloro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine(Single Enantiomer—Arbitrarily Assigned)

6-chloro-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 5, but replacing4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidine.ES/MS m/z: 340.1 [M+H].

Intermediate 433.6-chloro-3-fluoro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate but replacing4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)pyrimidineand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 358.0[M+H].

Intermediate 434.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 444.2 [M+H].

Intermediate 435.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-chloro-3-fluoro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 462.1 [M+H].

Intermediate 436. 8-bromo-6-chloro-2-isobutylimidazo[1,2-b]pyridazine

To a solution of 4-bromo-6-chloropyridazin-3-amine (400 mg, 1.9 mmol, 1equiv.) in DMF (3.8 mL) was added 1-chloro-4-methylpentan-2-one (310 mg,2.3 mmol, 1.2 equiv.). The reaction was heated to 70° C. and stirredovernight. The reaction was subsequently cooled to room temperature anddiluted with EtOAc/water. The resulting mixture was extracted twice withEtOAc, the combined organics were dried over MgSO₄, filtered and conc.in vacuo. The title compound was purified by silica gel chromatography(0-100% EtOAc/hexanes). ES/MS m/z: 244.10 [M+H].

Intermediate 437.6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-2-isobutylimidazo[1,2-b]pyridazine

6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-2-isobutylimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 59, but replacing3,3-dimethylpyrrolidine hydrochloride with7,7-difluoro-5-azaspiro[2.4]heptane and8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-2-isobutylimidazo[1,2-b]pyridazine. ES/MS m/z: 341.12[M+H].

Intermediate 438.8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-isobutylimidazo[1,2-b]pyridazine

8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-isobutylimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-2-isobutylimidazo[1,2-b]pyridazine.ES/MS m/z: 445.20 [M+H].

Intermediate 439.8-((1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropyl)-6-chloroimidazo[1,2-b]pyridazine.ES/MS m/z: 414.20 [M+H].

Intermediate 440.(1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-N-phenylcyclopropane-1-carboxamide

(1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-N-phenylcyclopropane-1-carboxamidewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-N-phenylcyclopropane-1-carboxamide.ES/MS m/z: 417.20 [M+H].

Intermediate 441.2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)propan-2-ol

2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)propan-2-olwas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)propan-2-ol.ES/MS m/z: 356.17 [M+H].

Intermediate 442.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 81, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 295.10 [M+1].

Intermediate 443.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile.ES/MS m/z: 399.19 [M+H].

Intermediate 444.3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrile

3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 81, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith4-fluoro-3-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 313.10 [M+1].

Intermediate 445.3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrile

3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrilewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrile.ES/MS m/z: 417.16 [M+H].

Intermediate 446.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrilewas prepared in the manner described for Intermediate 81, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 313.07 [M+1].

Intermediate 447.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile.ES/MS m/z: 417.19 [M+H].

Intermediate 448. potassiumtrifluoro((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)borate

4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolane(600 mg, 1.92 mmol) and KHF2 (1.05 g, 13.5 mmol) were weighed into avial, and MeOH (10 mL) and water (2 mL) were added. The mixture wasstirred at rt overnight, and then solvent was removed in vacuo. Theresulting residue was taken up in MeCN, and filtered to remove solids,washing with MeCN. The filtrate was concentrated in vacuo, then thesolid was washed with diethyl ether and dried to afford potassiumtrifluoro((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)borate. ¹HNMR (400 MHz, Acetone-d6) δ 7.45 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.1 Hz,2H), 1.74-1.62 (m, 1H), 0.88 (td, J=7.5, 2.7 Hz, 1H), 0.52 (d, J=9.8 Hz,1H), 0.07-−0.06 (m, 1H). ¹⁹F NMR (376 MHz, Acetone-d6) δ −62.88, −146.65(d, J=87.8 Hz).

Intermediate 449.5-bromo-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine

To a reaction vessel containing 5,7-dibromopyrazolo[1,5-a]pyrimidine(256 mg, 0.92 mmol, 1.2 equiv.),((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)trifluoro-14-borane,potassium salt (200 mg, 0.77 mmol, 1 equiv.), Pd(PPh₃)₄ (44 mg, 0.039mmol, 5 mol %) and Cs₂CO₃ (752 mg, 2.3 mmol, 3 equiv) was added afreshly degassed mixture of toluene/water (4.2 mL, 5:1 ratio) under anatmosphere of nitrogen. The reaction was heated to 90° C. for 4 hours.The reaction mixture was cooled to room temperature and diluted withEtOAc/water. The resulting mixture was extracted twice with EtOAc, thecombined organics were dried over MgSO₄, filtered and conc. in vacuo.The title compound was purified by FCC (0-30% EtOAc/hexanes). ES/MS m/z:350.00 [M+H].

Intermediate 450.7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine

7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-bromo-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 410.20 [M+H].

Intermediate 451.5-chloro-7-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 65, but replacing5,7-dichloropyrazolo[1,5-a]pyrimidine with5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine and3,3-dimethylpyrrolidine with (3R,4S)-3,4-difluoropyrrolidine-HCl. ES/MSm/z: 260.10 [M+H].

Intermediate 452.7-((3R,48)-3,4-difluoropyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

7-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 364.10 [M+H].

Intermediate 453.6-chloro-8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 59, but replacing3,3-dimethylpyrrolidine hydrochloride with3,3-difluoro-4-methoxypyrrolidine hydrochloride. ES/MS m/z: 307.00[M+H].

Intermediate 454.8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 411.15 [M+H].

Intermediate 455.6-chloro-8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 1,but replacing cyclopropylboronic acid with racemic2-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 322.02 [M+H].

Intermediate 456.8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-chloro-8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 426.10 [M+H].

Intermediate 457.7-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-oxa-7-azaspiro[4.4]nonane

7-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-oxa-7-azaspiro[4.4]nonane wasprepared in the manner described for Intermediate 10, but replacingpyrrolidine with 2-oxa-7-azaspiro[4.4]nonane. ES/MS m/z: 279.16 [M+H].

Intermediate 458.7-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-oxa-7-azaspiro[4.4]nonane

7-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-oxa-7-azaspiro[4.4]nonanewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-oxa-7-azaspiro[4.4]nonane.ES/MS m/z: 383.20 [M+H].

Intermediate 459.2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-8-oxa-2-azaspiro[4.5]decane

2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-8-oxa-2-azaspiro[4.5]decane wasprepared in the manner described for Intermediate 10, but replacingpyrrolidine with 8-oxa-2-azaspiro[4.5]decane. ES/MS m/z: 293.19 [M+H].

Intermediate 460.2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8-oxa-2-azaspiro[4.5]decane

2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8-oxa-2-azaspiro[4.5]decanewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-8-oxa-2-azaspiro[4.5]decane.ES/MS m/z: 397.20 [M+1-1].

Intermediate 461.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazole

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazoleas a racemate was prepared in the manner described for Intermediate 1,but replacing cyclopropylboronic acid with racemic6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazole.ES/MS m/z: 327.01 [M+H].

Intermediate 462.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)benzo[d]thiazole

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazoleas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazole.ES/MS m/z: 431.10 [M+H].

Intermediate 463.6-chloro-3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 1,but replacing 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and cyclopropylboronicacid with racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 372.10[M+H].

Intermediate 464.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-chloro-3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 476.17 [M+H].

Intermediate 465.6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 1,but replacing 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and cyclopropylboronicacid with racemic2-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 8-bromo-6-chloroimidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 368.09[M+H].

Intermediate 466.8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-5λ3-imidazo[1,2-b][1,2]fluorazine

8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-5λ3-imidazo[1,2-b][1,2]fluorazineas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 472.18 [M+H].

Intermediate 467.3-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

3-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 4-bromo-3-fluorobenzonitrile. ¹H NMR(400 MHz, DMSO-d₆) δ 7.77 (dd, J=10.3, 1.6 Hz, 1H), 7.59 (dd, J=8.1, 1.6Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 2.18 (dt, J=8.1, 5.5 Hz, 1H), 1.25-1.21(m, 1H), 1.20 (d, J=2.3 Hz, 12H), 1.16-1.10 (m, 1H), 0.35 (ddd, J=9.9,7.0, 5.6 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −119.15 (dd, J=10.3, 7.7Hz).

Intermediate 468.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrilewas prepared in the manner described for Intermediate 1, but replacingcyclopropylboronic acid with3-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 313.08 [M+H].

Intermediate 469.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile.ES/MS m/z: 417.14 [M+H].

Intermediate 470.6-chloro-8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

To racemic2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(150 mg, 0.43 mmol) in 1,4-dioxane (1.7 mL) was added8-bromo-6-chloro-1-imidazo[1,2-b]pyridazine (100 mg, 0.43 mmol, 1equiv), cataCXium A Pd G3 (31 mg, 0.04 mmol, 10 mol %), potassiumphosphate tribasic (228 mg, 1.1 mmol, 2.5 equiv), and water (0.36 mL).The mixture was sparged with Ar, sealed, and heated to 120° C. After 16h, the mixture was cooled to ambient temperature, filtered throughcelite, rinsed with EtOAc, and concentrated in vacuo. Purification bysilica gel chromatography (0-100% EtOAc/hexanes) affording6-chloro-8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate. ES/MS m/z: 372.08 [M+H].

Intermediate 471.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-chloro-8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 476.18 [M+H].

Intermediate 472. methyl4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Intermediate 470,but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith racemic methyl4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzoate.ES/MS m/z: 328.10 [M+H].

Intermediate 473. methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic methyl4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate.ES/MS m/z: 432.17 [M+H].

Intermediate 474. methyl3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Intermediate 470,but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith racemic methyl3-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzoate.ES/MS m/z: 328.10 [M+H].

Intermediate 475. methyl3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic methyl3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate.ES/MS m/z: 432.20 [M+H].

Intermediate 476.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid

To methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate(1.0 g, 2.5 mmol) in THF (15 mL) was added 2 M aqueous sodium hydroxide(6 mL, 12 mmol, 5 equiv) and the mixture was heated to 60° C. After 7.5h, the mixture was cooled to ambient temperature and acidified with 4MHCl in dioxane (6 mL). The volatiles were then removed under reducedpressure and the suspension was cooled to 0° C. overnight. The solidswere filtered, rinsed with water, and dried under N₂ to afford racemic4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid. ES/MS m/z: 418.20 [M+H].

Intermediate 477.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid

To methyl4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate(1.0 g, 2.5 mmol) in THF (15 mL) was added 2 M aqueous sodium hydroxide(6 mL, 12 mmol, 5 equiv) and the mixture was heated to 60° C. After 7.5h, the mixture was cooled to ambient temperature and acidified with 4MHCl in dioxane (6 mL). The volatiles were then removed under reducedpressure and the suspension was cooled to overnight. The solids werefiltered, rinsed with water, and dried under N₂ to afford4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid. ES/MS m/z: 390.10 [M+H].

Intermediate 478.3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid

3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid as a racemate was prepared in the manner described for Intermediate479, but replacing methyl4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoatewith racemic methyl3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate.ES/MS m/z: 390.14 [M+H].

Intermediate 479.2-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

2-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with2,6-dichloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 425.01 [M+H].

Intermediate 480.3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid

3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid as a racemate was prepared in the manner described for Intermediate476, but replacing methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoatewith racemic methyl3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate.ES/MS m/z: 418.16 [M+H].

Intermediate 481.6-chloro-8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 470,but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane.ES/MS m/z: 353.99 [M+H].

Intermediate 482.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-chloro-8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 458.07 [M+H].

Intermediate 483.4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrilewas prepared in the manner described for Intermediate 470, but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine andcyclopropylboronic acid with3-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 331.00 [M+H].

Intermediate 484.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile.ES/MS m/z: 435.00 [M+H].

Intermediate 485.5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)nicotinonitrile

5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrileas a racemate was prepared in the manner described for Intermediate 470,but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith racemic5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)nicotinonitrile.ES/MS m/z: 296.00 [M+H].

Intermediate 486.5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)nicotinonitrile

5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrileas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrile.ES/MS m/z: 400.12 [M+H].

Intermediate 487. methyl4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Intermediate 470,but replacing 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith racemic methyl4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzoate.ES/MS m/z: 346.00 [M+H].

Intermediate 488. methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic methyl4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate.ES/MS m/z: 450.06 [M+H].

Intermediate 489.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid

To methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate(488 mg, 1.1 mmol) in THF (2.2 mL) and MeOH (1.0 mL was added 2 Maqueous lithium hydroxide (2.7 mL, 5.4 mmol, 5 equiv) and the mixturewas heated to 60° C.

After 1 h, the reaction was cooled to ambient temperature, 4 M HCl in1,4-dioxane was added (2 mL), and the resulting mixture was concentratedin vacuo. To the crude material was added MeOH (10 mL) and 1 M aqueousHCl (10 mL) and the mixture was heated to 80° C. After 24 h, the mixturewas diluted with water (50 mL) and cooled to 0° C. Isolation byfiltration afforded4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid. ES/MS m/z: 408.00 [M+H].

Intermediate 490.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 470, but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneacid with5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 392.00 [M+H].

Intermediate 491.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 496.05 [M+H].

Intermediate 492.6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 470, but replacing8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 409.96 [M+H].

Intermediate 493.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 514.09 [M+H].

Intermediate 494.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 470, but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 392.00 [M+H].

Intermediate 495.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 496.05 [M+H].

Intermediate 496.6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 470, but replacing8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 409.96 [M+H].

Intermediate 497.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 514.09 [M+H].

Intermediate 498.5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole

To racemic((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)boronicacid (50 mg, 0.21 mmol), 5-bromo-2-methylbenzo[d]thiazole (96 mg, 0.42mmol, 2 equiv), cataCXium A Pd G3 (31 mg, 0.04 mmol, 0.2 equiv), andpotassium phosphate tribasic (112 mg, 0.53 mmol, 2.5 equiv) in1,4-dioxane (1 mL) and water (0.2 mL) was sparged with Ar, sealed, andheated 85° C. After 2 h, the mixture was filtered through celite, rinsedwith EtOAc, and concentrated in vacuo. Purification by silica gelchromatography (0-100% EtOAc/hexanes) afforded5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazoleas a racemate. ES/MS m/z: 341.00 [M+H].

Intermediate 499.5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole

5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazoleas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole.ES/MS m/z: 445.08 [M+H].

Intermediate 500.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 470, but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole.ES/MS m/z: 392.00 [M+H].

Intermediate 501.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 496.10 [M+H].

Intermediate 502.6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 470, but replacing8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole.ES/MS m/z: 410.00 [M+H].

Intermediate 503.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 514.10 [M+H].

Intermediate 504.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 470, but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole.ES/MS m/z: 392.00 [M+H].

Intermediate 505.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 496.10 [M+H].

Intermediate 506.6-chloro-8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 498,but replacing 5-bromo-2-methylbenzo[d]thiazole with6-bromo-1-methyl-1H-indazole. ES/MS m/z: 324.00 [M+H].

Intermediate 508.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazineas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-chloro-8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 428.10 [M+H].

Intermediate 509.5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-(trifluoromethyl)benzo[d]isoxazole

5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-(trifluoromethyl)benzo[d]isoxazoleas a racemate was prepared in the manner described for Intermediate 498,but replacing 5-bromo-2-methylbenzo[d]thiazole with5-bromo-3-(trifluoromethyl)benzo[d]isoxazole. ES/MS m/z: 379.00 [M+H].

Intermediate 510.5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-(trifluoromethyl)benzo[d]isoxazole

5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-(trifluoromethyl)benzo[d]isoxazoleas a racemate was prepared in the manner described for Intermediate 18,but replacing 6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazinewith racemic5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-(trifluoromethyl)benzo[d]isoxazole.ES/MS m/z: 483.00 [M+H].

Intermediate 511.2,6-dichloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine

2,6-dichloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 10, but replacing8-bromo-6-chloroimidazo[1,2-b]pyridazine with2,6,8-trichloroimidazo[1,2-b]pyridazine and pyrrolidine with3,3-difluoro-4,4-dimethylpyrrolidine. ES/MS m/z: 320.98 [M+H].

Intermediate 512.8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 454.20 [M+H].

Intermediate 513.1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol

A solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (1800mg, 5.35 mmol), 4,4-difluoropyrrolidin-3-ol (1.07 g, 5.35 mmol), DIPEA(2.8 mL, 16.1 mmol) in DMF (10 mL) was heated to 110° C. After 20 hours,the reaction mixture was diluted with EtOAc washed with brine, driedover Na₂SO₄, filtered, organic residue was purified by SiO₂chromatography (0-100% EtOAc/Hex), affording1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 379.20 [M+H].

Intermediate 514.8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

NaH (16 mg, 0.42 mmol, 60% in mineral oil) was added to the solution of1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(80 mg, 0.21 mmol) in DMF (3 ml), then2-fluoro-4-(trifluoromethyl)pyridine (70 mg, 0.42 mol) was added to thereaction mixture and was heated to 85° C. for 4 hours, the reactionmixture was cooled to room temperature. The layers were separated, andthe aqueous layer was extracted with EtOAc (3×200 mL). The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-100% EtOAc/Hex),affording8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 524.20 [M+H].

Intermediate 515.8-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 514, but replacingfluoro-4-(trifluoromethyl)pyridine with5-(difluoromethoxy)-2-fluoropyridine. ES/MS m/z: 522.20 [M+H].

Intermediate 516.8-(3,3-difluoro-4-((5-(trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3,3-difluoro-4-((5-(trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 514, but replacingfluoro-4-(trifluoromethyl)pyridine with2-fluoro-4-(trifluoromethoxy)pyridine. ES/MS m/z: 540.20 [M+H].

Intermediate 517.8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-3/1)imidazo[1,2-b]pyridazine

8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 514, but replacingfluoro-4-(trifluoromethyl)pyridine with2-fluoro-5-(perfluoroethoxy)pyridine. ES/MS m/z: 590.20 [M+H].

Intermediate 518.6-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-3/1)oxy)nicotinonitrile

6-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrilewas prepared in the manner described for Intermediate 514, but replacingfluoro-4-(trifluoromethyl)pyridine with 6-fluoronicotinonitrile. ES/MSm/z: 481.20 [M+H].

Intermediate 519.8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 514, but replacingfluoro-4-(trifluoromethyl)pyridine with2-fluoro-5-(trifluoromethyl)pyrazine. ES/MS m/z: 525.20 [M+H].

Intermediate 520.S)-8-(4-((4-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

(S)-8-(4-((4-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 514, but replacingfluoro-4-(trifluoromethyl)pyridine with4-(difluoromethyl)-2-fluoropyridine. ES/MS m/z: 506.20 [M+H].

Intermediate 521.(S)-2-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-3/1)oxy)isonicotinonitrile

(S)-2-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)isonicotinonitrilewas prepared in the manner described for Intermediate 514, but replacingfluoro-4-(trifluoromethyl)pyridine with 2-fluoroisonicotinonitrile.ES/MS m/z: 481.20 [M+H].

Intermediate 522.6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared as follows: To a mixture of8-bromo-6-chloro-imidazo[1,2-b]pyridazine (0.2 g, 0.86 mmol) andpotassium carbonate (0.24 g, 1.72 mmol) in EtOH (2 mL) was added3,3,4,4-tetrafluoropyrrolidine hydrochloride (154 mg, 0.86 mmol). Thereaction mixture was heated at 90° C. overnight. The solvent was thenevaporated and the residue was purified with Prep HPLC to afford6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 392.20 [M+H].

Intermediate 523.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared as follows: To a mixture of6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine(24 mg, 0.082 mmol) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (30mg, 0.16 mmol) in 1,4-dioxane (1.5 mL) and water (0.75 mL) were addedPd(dppf)Cl₂·CH₂Cl₂ (7 mg, 0.008 mmol) and cesium carbonate (53 mg, 0.16mmol). The reaction mixture was heated at 80° C. for 1 h. The reactionmixture was then filtered and was purified with Prep HPLC to afford6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 399.10 [M+H].

Intermediate 524.5-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-5-azaspiro[2.4]heptan-7-ol

5-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-5-azaspiro[2.4]heptan-7-olwas prepared in the manner described for Intermediate 513, but replacing4,4-difluoropyrrolidin-3-ol with 5-azaspiro[2.4]heptan-7-ol. ES/MS m/z:369.20.

Intermediate 525.6-(2,4-dimethoxypyrimidin-5-yl)-8-(7-((5-(trifluoromethyl)pyridin-2-1/1)oxy)-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]

5-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-5-azaspiro[2.4]heptan-7-ol(60 mg, 0.16 mmol) was dissolved in NMP (1 mL), to the reaction mixturewas added 2-fluoro-5-(trifluoromethyl)pyridine (54 mg, 0.326 mmol). Thereaction mixture was heated at 85° C. for 4h, the reaction mixture wasthen filtered and purified with Prep HPLC to afford6-(2,4-dimethoxypyrimidin-5-yl)-8-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b].ES/MS m/z: 514.20.

Intermediate 526.5-chloro-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 522, but replacing8-bromo-6-chloroimidazo[1,2-b]pyridazine with5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine. ES/MS m/z: 296.00.

Intermediate 527.5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith5-chloro-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 400.10.

Intermediate 528.5-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 522, but replacing8-bromo-6-chloroimidazo[1,2-b]pyridazine with7,7-difluoro-5-azaspiro[2.4]heptane. ES/MS m/z: 286.00

Intermediate 529.7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith5-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 390.20.

Intermediate 530.5-chloro-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

5-chloro-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 522, but replacing8-bromo-6-chloroimidazo[1,2-b]pyridazine with5,7-dichloropyrazolo[1,5-a]pyrimidine. ES/MS m/z: 295.00.

Intermediate 531.5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine

5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith5-chloro-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 399.20.

Intermediate 532.6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 350.20 [M+H].

Intermediate 533.8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 454.20 [M+H].

Intermediate 534.6-chloro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(Racemic Mixture)

6-chloro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane.ES/MS m/z: 354.20 [M+H].

Intermediate 535.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 458.20 [M+H].

Intermediate 536.6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 350.20 [M+H].

Intermediate 537. 6-bromo-1-(3,3,3-trifluoropropyl)-1H-indazole

6-bromo-1-(3,3,3-trifluoropropyl)-1H-indazole was prepared in the mannerdescribed for Intermediate 191, but replacing 2,2,2-trifluoroethyltrifluoromethanesulfonate with 3,3,3-trifluoropropyltrifluoromethanesulfonate. ES/MS m/z: 293.00 [M+H].

Intermediate 538.6-chloro-8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 498, but replacing5-bromo-2-methylbenzo[d]thiazole with6-bromo-1-(3,3,3-trifluoropropyl)-1H-indazole. ES/MS m/z: 406.10 [M+H].

Intermediate 539.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith 6-chloro-8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 510.20 [M+H].

Intermediate 540.6-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile

6-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile was preparedin the manner described for Intermediate 191, but replacing6-bromo-1H-indazole with 6-bromo-1H-indazole-3-carbonitrile. ES/MS m/z:304.00 [M+H].

Intermediate 541.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrilewas prepared in the manner described for Intermediate 498, but replacing5-bromo-2-methylbenzo[d]thiazole with6-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile ES/MS m/z:417.10 [M+H].

Intermediate 542.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrilewas prepared in the manner described for Intermediate 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile.ES/MS m/z: 521.20 [M+H].

Intermediate 543.6-chloro-8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate498, but replacing 5-bromo-2-methylbenzo[d]thiazole with2-bromo-5-(2,2,2-trifluoroethoxy)pyridine. ES/MS m/z: 369.10 [M+H].

Intermediate 544.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 473.20 [M+H].

Intermediate 545.2-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(trifluoromethyl)thiazole

2-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(trifluoromethyl)thiazole(racemic mixture) was prepared in the manner described for Intermediate498 but replacing 5-bromo-2-methylbenzo[d]thiazole with2-bromo-5-(trifluoromethyl)thiazole. ES/MS m/z: 345.00 [M+H].

Intermediate 546.2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(trifluoromethyl)thiazole

2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(trifluoromethyl)thiazoleas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith2-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(trifluoromethyl)thiazole(racemic mixture). ES/MS m/z: 449.10 [M+H].

Intermediate 547.5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)thiazole

5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)thiazole(racemic mixture) was prepared in the manner described for Intermediate498, but replacing 5-bromo-2-methylbenzo[d]thiazole with5-bromo-2-(trifluoromethyl)thiazole. ES/MS m/z: 345.00 [M+H].

Intermediate 548.5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)thiazole

5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)thiazoleas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)thiazole(racemic mixture). ES/MS m/z: 449.10 [M+H].

Intermediate 549.6-chloro-8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate498, but replacing 5-bromo-2-methylbenzo[d]thiazole with4-bromo-1-(trifluoromethyl)pyrazole. ES/MS m/z: 328.10 [M+H].

Intermediate 550.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 432.20 [M+H].

Intermediate 551.2-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(trifluoromethyl)thiazole

2-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(trifluoromethyl)thiazole(racemic mixture) was prepared in the manner described for Intermediate498, but replacing 5-bromo-2-methylbenzo[d]thiazole with2-bromo-4-(trifluoromethyl)thiazole. ES/MS m/z: 345.00 [M+H].

Intermediate 552.2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(trifluoromethyl)thiazole

2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(trifluoromethyl)thiazoleas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith2-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(trifluoromethyl)thiazole(racemic mixture). ES/MS m/z: 449.10 [M+H].

Intermediate 553.6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine

8-bromo-6-chloro-imidazo[1,2-b]pyridazine (250 mg, 1.08 mmol) and1-(difluoromethyl)-4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)cyclopropyl]pyrazole(342 mg, 1.08 mmol) were dissolved in 1,4-dioxane (4 ml) and water (2ml). To the above mixture were added[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (88 mg, 0.1 mmol) and Cs₂CO₃ (701 mg, 2.15 mmol).The reaction mixture was then heated at 120 degrees for 1 hour. Thereaction mixture was then filtered and purified with Prep HPLC to afford6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 310.10 [M+H].

Intermediate 554.8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 414.20 [M+H].

Intermediate 555.6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described for Intermediate238, but replacing racemic2-[(1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith racemicR1S,2S)-2-[1-(difluoromethyl)pyrazol-3-yl]cyclopropyl]boronic acid.ES/MS m/z: 310.10 [M+H].

Intermediate 556.8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 414.20 [M+H].

Intermediate 557.6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith racemic1-(difluoromethyl)-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1H-pyrazoleand 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 328.10[M+H].

Intermediate 558.8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine(racemic mixture) (racemic mixture). ES/MS m/z: 432.20 [M+H].

Intermediate 559.6-chloro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith racemic2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-5-(trifluoromethoxy)pyridine.ES/MS m/z: 355.10 [M+H].

Intermediate 560.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 459.20 [M+H].

Intermediate 561.6-chloro-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith racemic2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-5-(trifluoromethoxy)pyridine.ES/MS m/z: 373.10 [M+H].

Intermediate 562.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 477.20 [M+H].

Intermediate 563.5-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrile

5-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrile(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith racemic5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)picolinonitrile.ES/MS m/z: 314.10 [M+H].

Intermediate 564.5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrile

5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrileas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith5-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrile(racemic mixture). ES/MS m/z: 418.20 [M+H].

Intermediate 565.6-chloro-8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethoxy)pyridine.ES/MS m/z: 355.10 [M+H].

Intermediate 566.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 459.20 [M+H].

Intermediate 567.6-chloro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith racemic2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-5-(trifluoromethyl)pyrimidine.ES/MS m/z: 340.10 [M+H].

Intermediate 568.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 444.20 [M+H].

Intermediate 569.6-chloro-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith racemic2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-5-(trifluoromethyl)pyrimidineand 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 358.10[M+H].

Intermediate 570.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 462.20 [M+H].

Intermediate 571.6-chloro-8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) was prepared in the manner described Intermediate 238,but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith racemic5-(difluoromethyl)-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine.ES/MS m/z: 321.10 [M+H].

Intermediate 572.8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineas racemic mixture was prepared in the manner described for Intermediate174, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 425.20 [M+H].

Intermediate 573.6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

Step 1: To a solution of 6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one(2 g, 8.4 mmol) in DMF was added potassium carbonate (2.3 g, 16.8 mmol)and 2,2,2-Trifluoroethyl trifluoromethanesulfonate (2.9 g, 12.6 mmol).The reaction mixture was heated to 100° C. overnight. Then the reactionmixture was cooled to RT, diluted with brine (50 mL), and extracted with80% EtOAc/Hex (2×100 mL). The combined organic layers were concentratedand purified by SiO₂ chromatography to afford6′-bromo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 320.20.

Step 2: A solution of Potassium vinyltrifluoroborate (3.52 g, 26.2mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.8g, 2.5 mmol), potassium carbonate (7.6 g, 55 mmol) and6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one (8 g, 25 mmol) wereadded to THF/H₂O (9/1, 45 mL). The reaction mixture was heated to 85° C.After 20 hours, the reaction mixture was cooled to RT. Reaction mixturewas filtered and diluted with EtOAc, organic layer was washed with brineand then evaporated under vacuum. The residue was purified withCombi-Flash column to afford1′-(2,2,2-trifluoroethyl)-6′-vinylspiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 268.10. ¹H NMR (400 MHz, DMSO-d₆) δ 7.45 (s, 1H), 7.14 (dd,J=7.7, 1.4 Hz, 1H), 7.09-6.95 (m, 1H), 6.75 (dd, J=17.6, 10.9 Hz, 1H),5.89 (dd, J=17.6, 1.0 Hz, 1H), 5.28 (dd, J=10.9, 1.0 Hz, 1H), 4.82-4.60(m, 2H), 1.78-1.66 (m, 2H), 1.61 (q, J=4.8, 4.0 Hz, 2H). ¹⁹F NMR (376MHz, DMSO-d₆) δ −69.25 (td, J=9.5, 6.1 Hz).

Step 3: To a cooled (0° C.) solution of1′-(2,2,2-trifluoroethyl)-6′-vinylspiro[cyclopropane-1,3′-indolin]-2′-one(759 mg, 2.84 mmol) and (R)-Pheox Ru catalyst (90 mg, 0.14 mmol) in 4 mLCH₂Cl₂ was added a 0.2M solution of 1,3-dioxoisoindolin-2-yl2-diazoacetate (722 mg, 3.12 mmol) in CH₂Cl₂ over 20 minutes. Thereaction mixture was stirred at 0° C. for 1 h. The reaction was thenquenched with MeOH, evaporated solvent and the residue was purified withCombi-Flash column to afford1,3-dioxoisoindolin-2-yl(1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropane-1-carboxylate.ES/MS m/z: 471.10. ¹H NMR (400 MHz, DMSO-d₆) δ 8.08-7.89 (m, 4H), 7.19(s, 1H), 7.06-7.01 (m, 2H), 4.70 (q, J=9.6, 9.1 Hz, 2H), 2.76 (ddd,J=9.3, 7.0, 4.1 Hz, 1H), 1.76 (ddt, J=14.4, 4.9 Hz, 2H), 1.69 (q, J=4.0,3.2 Hz, 2H), 1.60 (dt, J=4.7, 2.8 Hz, 2H), 1.18 (t, J=7.1 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d₆) δ −69.29 (t, J=9.4 Hz).

Step 4: Under Argon, a microwave vial was charged with(1,3-dioxoisoindolin-2-yl)(1S,2S)-2-[2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indoline]-6′-yl]cyclopropanecarboxylate(325 mg, 0.69 mmol), Bis(pinacolato)diboron (263 mg, 1.04 mmol), methylisonicotinate (47 mg, 0.345 mmol) and EtOAc (3 ml). The resultingmixture was heated to ° C. for 1 h. Then the solvent was evaporated andthe residue was purified with combi-flash to afford6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 408.20.

Intermediate 574.6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-F-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 470, but replacing2-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-oneand 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 451.10.

Intermediate 575.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 555.20.

Intermediate 576.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-F-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared as a racemic mixture in the manner described forIntermediate 498, but replacing 5-bromo-2-methylbenzo[d]thiazole with6′-bromo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 433.10.

Intermediate 577.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared in the manner described for 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)Spiro[cyclopropane-1,3′-indolin]-2′-one (racemate). ES/MS m/z: 537.20.

Intermediate 578.6′-bromo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

Added NaH (167 mg, 4.36 mmol, 60% in mineral oil) to the solution of6-bromo-1H-indazole (537 mg, 2.73 mmol) in DMF (6 mL), stirred at RT for10 mins, then to the reaction mixture was added2-fluoro-5-(trifluoromethyl)pyridine (900 mg, 5.45 mmol) and thereaction mixture was stirred at 85 C for 4 h. Then the reaction mixturewas diluted with EtOAc, washed with brine, purified with combi-flashcolumn to afford6′-bromo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.

Intermediate 579.6-chloro-8-((1S,2S)-2-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemate) was prepared in the manner described for Intermediate 498,but replacing 5-bromo-2-methylbenzo[d]thiazole with6-bromo-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazole. ES/MS m/z:455.10.

Intermediate 580.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemate) was prepared in the manner described for 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemate). ES/MS m/z: 559.20.

Intermediate 581.6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-F-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 573, but replacing6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one with6′-bromospiro[cyclobutane-1,3′-indolin]-2′-one. ES/MS m/z: 422.20.

Intermediate 582.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-F-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-oneprepared in the manner described Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one.ES/MS m/z: 447.10.

Intermediate 583.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-onewas prepared in the manner described for 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one.ES/MS m/z: 551.20.

Intermediate 584.6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-F-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-onewas prepared in the manner described Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one.ES/MS m/z: 465.10.

Intermediate 585.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-onewas prepared in the manner described for 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one.ES/MS m/z: 569.20.

Intermediate 586.6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1‘-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3’-indolin]-2′-one wasprepared in the manner described for Intermediate 573, but replacing6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one with6′-bromospiro[cyclopentane-1,3′-indolin]-2′-one. ES/MS m/z: 436.20.

Intermediate 587.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-onewas prepared in the manner described Intermediate 238 but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one.ES/MS m/z: 461.10.

Intermediate 588.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-onewas prepared in the manner described for 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one.ES/MS m/z: 565.20.

Intermediate 589.6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1‘-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3’-indolin]-2′-one wasprepared in the manner described Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-oneand 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 479.10.

Intermediate 590.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-onewas prepared in the manner described for 523, but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one.ES/MS m/z: 583.20.

Intermediate 591.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]quinoline(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]quinoline(racemic mixture). ES/MS m/z: 321.10 [M+H].

Intermediate 592. 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine

To a solution of 4-bromo-6-chloro-pyridazin-3-amine (200 mg, 0.959 mmol)in IPA (2 mL) was added N,N-dimethylformamide dimethyl acetal (0.332 mL,2.49 mmol). The resulting mixture was heated to 80° C. for 3 h, thencooled to rt and hydroxylamine hydrochloride (100 mg, 1.44 mmol) wasadded. The mixture was heated to 50° C. and stirred for 3 h, then cooledto rt, quenched with 10% NaHCO3 aqueous solution, and extracted twicewith 2-MeTHF. Combined organics were dried over MgSO4, filtered, andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (0-100% EtOAc/hexanes) to affordN-(4-bromo-6-chloropyridazin-3-yl)-N′-hydroxyformimidamide. ES/MS m/z:251.0 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.39 (d, J=1.2Hz, 1H), 8.24 (d, J=9.6 Hz, 1H), 8.04 (d, J=9.4 Hz, 1H).

T3P (0.156 mL, 0.262 mmol) was added to a solution ofN-(4-bromo-6-chloropyridazin-3-yl)-N′-hydroxyformimidamide (44 mg, 0.175mmol) in THF (0.5 mL), and the mixture was heated to 55° C. for 2 h. Thereaction mixture was allowed to cool to rt, quenched with 10% NaHCO3aqueous solution, and extracted twice with EtOAc. Combined organics weredried over MgSO4, filtered, and concentrated in vacuo. The resultingresidue was purified by silica gel chromatography (0-100% EtOAc/hexanes)to afford 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine. ES/MS m/z:233.0 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.41 (s, 1H).

Intermediate 593.4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolane

4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolanewas prepared in the manner described for Intermediate 72, but replacing2-chloro-5-vinylbenzonitrile with 1-(trifluoromethyl)-4-vinyl-benzene.¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz,2H), 2.16-2.07 (m, 1H), 1.20 (d, J=4.6 Hz, 12H), 1.14-1.08 (m, 2H),0.32-0.21 (m, 1H).

Intermediate 594.((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)trifluoro-14-borane,Potassium Salt

((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)trifluoro-14-borane,potassium salt was prepared in the manner described for Intermediate448, but replacing4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolanewith2-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Intermediate 595.2-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

2-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared in the manner described for Intermediate 72, but replacing5-bromo-2-chlorobenzonitrile with 1-bromo-4-(difluoromethyl)benzene. ¹HNMR (400 MHz, DMSO-d₆) δ 7.47-7.38 (m, 2H), 7.22 (d, J=8.0 Hz, 2H), 6.96(t, J=56.0 Hz, 1H), 2.09-2.02 (m, 1H), 1.19 (d, J=4.5 Hz, 12H),1.10-1.01 (m, 2H), 0.23 (ddd, J=8.9, 7.5, 5.4 Hz, 1H).

Intermediate 596.6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine was preparedas follows: To a mixture of 8-bromo-6-chloro-imidazo[1,2-b]pyridazine(150 mg, 0.645 mmol) and 3-phenylazetidine hydrochloride (109 mg, 0.645mmol) in MeCN (2 mL) was added N,N-diisopropylethylamine (0.337 mL, 1.94mmol). The mixture was heated to 100° C. and stirred for 4 h. Themixture was then concentrated in vacuo and the resulting residue waspurified by silica gel chromatography (0-100% EtOAc/hexanes) to afford6-chloro-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MS m/z:285.1 [M+H].

Intermediate 597.6-chloro-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazine

6-chloro-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 3-(trifluoromethyl)azetidine. ES/MSm/z: 277.1 [M+H].

Intermediate 598.6-chloro-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 3,3-dimethylazetidinehydrochloride. ES/MS m/z: 237.1 [M+H].

Intermediate 599.6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with3-fluoro-3-(trifluoromethyl)azetidine hydrochloride. ES/MS m/z: 295.0[M+H].

Intermediate 600.6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 2-azaspiro[3.3]heptane. ES/MS m/z:249.1 [M+H].

Intermediate 601.6-chloro-8-(3-(difluoromethyl)-3-methylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-(difluoromethyl)-3-methylazetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with3-(difluoromethyl)-3-methylazetidine hydrochloride. ES/MS m/z: 273.1[M+H].

Intermediate 602.6-chloro-8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with3-(2,2-difluorocyclopropyl)azetidine 2,2,2-trifluoroacetate. ES/MS m/z:285.1 [M+H].

Intermediate 603.6-chloro-8-(3-cyclobutylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-cyclobutylazetidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 3-cyclobutylazetidinehydrochloride. ES/MS m/z: 263.1 [M+H].

Intermediate 604.5-chloro-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3-fluoro-3-(trifluoromethyl)azetidine hydrochloride and5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine, respectively. ES/MS m/z:296.1 [M+H].

Intermediate 605.6-chloro-8-(3-(difluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-(difluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 3-(difluoromethyl)azetidinehydrochloride. ES/MS m/z: 259.1 [M+H].

Intermediate 606.6-chloro-8-(3-cyclopropylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-cyclopropylazetidin-1-yl)imidazo[1,2-b]pyridazine wasprepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 3-cyclopropylazetidinehydrochloride. ES/MS m/z: 349.1 [M+H].

Intermediate 607.6-chloro-8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 5,5-difluoro-2-azaspiro[3.3]heptane2,2,2-trifluoroacetate. ES/MS m/z: 285.1 [M+H].

Intermediate 608.6-chloro-8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 1,1-difluoro-5-azaspiro[2.3]hexanehydrochloride. ES/MS m/z: 271.1 [M+H].

Intermediate 609.6-chloro-8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 3-(2-fluoropropan-2-yl)azetidinehydrochloride. ES/MS m/z: 269.1 [M+H].

Intermediate 610.5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride and5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine, respectively, and runningthe reaction at rt for 1 h. ES/MS m/z: 288.1 [M+H].

Intermediate 611.7-chloro-5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-a]pyrimidine

7-chloro-5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-a]pyrimidinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride and5,7-dichloroimidazo[1,2-a]pyrimidine, respectively, and running thereaction at 0° C. for 10 min. ES/MS m/z: 287.1 [M+H].

Intermediate 612.8-bromo-6-chloro-2-cyclopropyl-3-fluoroimidazo[1,2-b]pyridazine

To a solution of 8-bromo-6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine(400 mg, 1.47 mmol, 1 equiv) in acetonitrile (6.3 mL) was addedSelectFluor (520 mg, 1.47 mmol, 1 equiv). The reaction mixture washeated to 40° C. and stirred for 16 h. The reaction mixture wassubsequently concentrated in vacuo. The resulting residue was dissolvedin a mixture of EtOAc/water, extracted twice with EtOAc, the combinedorganics were dried over MgSO₄, filtered and concentrated in vacuo.8-bromo-6-chloro-2-cyclopropyl-3-fluoroimidazo[1,2-b]pyridazine waspurified by silica gel chromatography (0-50% EtOAc/hexanes). ES/MS m/z:290.00 [M+H].

Intermediate 613.6-chloro-2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride and8-bromo-6-chloro-2-cyclopropyl-3-fluoroimidazo[1,2-b]pyridazine,respectively. ES/MS m/z: 345.1 [M+H].

Intermediate 614.8-bromo-6-chloro-3-fluoro-2-methylimidazo[1,2-b]pyridazine

8-bromo-6-chloro-3-fluoro-2-methylimidazo[1,2-b]pyridazine was preparedin the manner described for Intermediate 612, but replacing8-bromo-6-chloro-2-cyclopropylimidazo[1,2-b]pyridazine with8-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine. ES/MS m/z: 263.93[M+H].

Intermediate 615.6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoro-2-methylimidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoro-2-methylimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride and8-bromo-6-chloro-3-fluoro-2-methylimidazo[1,2-b]pyridazine,respectively. ES/MS m/z: 319.1 [M+H].

Intermediate 616. 8-bromo-6-chloro-2-isobutylimidazo[1,2-b]pyridazine

To a solution of 4-bromo-6-chloropyridazin-3-amine (400 mg, 1.9 mmol, 1equiv.) in DMF (3.8 mL) was added 1-chloro-4-methylpentan-2-one (310 mg,2.3 mmol, 1.2 equiv.). The reaction was heated to 70° C. and stirredovernight. The reaction was subsequently cooled to room temperature anddiluted with EtOAc/water. The resulting mixture was extracted twice withEtOAc, the combined organics were dried over MgSO₄, filtered and conc.in vacuo. The title compound was purified by silica gel chromatography(0-100% EtOAc/hexanes). ES/MS m/z: 244.10 [M+H].

Intermediate 617.8-bromo-6-chloro-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine

8-bromo-6-chloro-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 616, but replacing1-chloro-4-methylpentan-2-one with2-bromo-1-(1-(trifluoromethyl)cyclopropyl)ethan-1-one. ES/MS m/z: 339.90[M+H].

Intermediate 618.6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3,3-difluoro-4,4-dimethylpyrrolidine hydrochloride and8-bromo-6-chloro-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine,respectively. ES/MS m/z: 395.1 [M+H].

Intermediate 619.6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with7,7-difluoro-5-azaspiro[2.4]heptane and8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine, respectively, andrunning the reaction at 40° C. for 1 h. ES/MS m/z: 286.1 [M+H].

Intermediate 620.6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin

6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride and8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine, respectively, andrunning the reaction at 40° C. for 1 h. ES/MS m/z: 288.1 [M+H].

Intermediate 621.(R)-6-chloro-8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine

(R)-6-chloro-8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with(3R)-3-(trifluoromethoxy)pyrrolidine hydrochloride and8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine, respectively, andrunning the reaction at 40° C. for 1 h. ES/MS m/z: 308.0 [M+H].

Intermediate 622.1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol

1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with4,4-difluoropyrrolidin-3-ol hydrochloride and8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine, respectively, andrunning the reaction at 40° C. for 1 h. ES/MS m/z: 276.1 [M+H].

Intermediate 623.6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride and8-bromo-6-chloro-imidazo[1,2-b]pyridazine with3-fluoro-3-(trifluoromethyl)azetidine hydrochloride and8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine, respectively, andrunning the reaction at 40° C. for 1 h. ES/MS m/z: 296.1 [M+H].

Intermediate 624.1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-(trifluoromethyl)azetidin-3-ol

1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-(trifluoromethyl)azetidin-3-olwas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with 3-(trifluoromethyl)azetidin-3-olhydrochloride, and running the reaction at 85° C. for 1 h. ES/MS m/z:293.1 [M+H].

Intermediate 625.(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanol

(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanolwas prepared in the manner described for Intermediate 596, but replacing3-phenylazetidine hydrochloride with (3-fluoroazetidin-3-yl)methanol,and running the reaction at 85° C. for 1 h. ES/MS m/z: 257.1 [M+H].

Intermediate 626.6-chloro-8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared as follows: To a mixture of1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(44 mg, 0.160 mmol) and cesium carbonate (130 mg, 0.399 mmol) in NMP (1mL) was added 2-fluoro-5-(trifluoromethyl)pyridine (0.039 mL, 0.319mmol), and the mixture heated to 60° C. for 1 h. The mixture was thencooled to rt, diluted with EtOAc, and washed with brine. Combinedorganics were dried over MgSO₄, filtered, and concentrated in vacuo. Theresulting residue was purified by silica gel chromatography (0-100%EtOAc/hexanes) to afford6-chloro-8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 421.1 [M+H].

Intermediate 627.6-chloro-8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 626, but replacing1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-(trifluoromethyl)azetidin-3-ol.ES/MS m/z: 438.1 [M+H].

Intermediate 628.6-chloro-8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-chloro-8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 626, but replacing1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanol.ES/MS m/z: 402.1 [M+H].

Intermediate 629.1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate

1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate was prepared as follows: To a solutionof1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(44 mg, 0.160 mmol) in DMF (1 mL) at 0° C. was added NaH (7.3 mg, 0.192mmol). The mixture was stirred at 0° C. for 30 min, after which1,1,1-trifluoro-2-isocyanato-ethane (30 mg, 0.239 mmol) was added. Themixture was stirred overnight, allowing to warm to rt. Additional NaH(15 mg, 0.375 mmol) was added, followed by additional1,1,1-trifluoro-2-isocyanato-ethane (60 mg, 0.480 mmol), and the mixturestirred for 1 h. Another portion of both NaH (15 mg, 0.375 mmol) and1,1,1-trifluoro-2-isocyanato-ethane (60 mg, 0.480 mmol) were added, andthe mixture stirred at rt for 16 h. The mixture was then quenched withH₂O and extracted with EtOAc. Combined organics were dried over MgSO₄,filtered, and concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (0-100% EtOAc/hexanes) to afford1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate.ES/MS m/z: 401.1 [M+H].

Intermediate 630.(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate

(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate was prepared in the manner described forIntermediate 629, but replacing1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanol.ES/MS m/z: 382.1 [M+H].

Intermediate 631.3-((6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate

To a solution of 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine (200mg, 0.86 mmol) and 2,2-difluoropropane-1,3-diol (288 mg, 2.6 mmol) inTHF (10 mL) at 0° C. was added NaH (39 mg, 1.70 mmol). The mixture wasstirred overnight, allowing to warm to rt, then quenched with H₂O andextracted with EtOAc. Combined organics were dried over MgSO₄, filtered,and concentrated in vacuo. The residue was purified by silica gelchromatography (0-100% EtOAc/hexanes) to afford3-((6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol.ES/MS m/z: 265.1 [M+H].

To a solution of3-((6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol(90 mg, 0.34 mmol) in DCM (2 mL) was added DIPEA (0.59 mL, 3.4 mmol),followed by 2-isocyanatopropane (0.33 mL, 3.4 mmol). The mixture wasstirred at 50° C. for 2 h, then cooled to rt, concentrated in vacuo, andpurified by silica gel chromatography (0-100% EtOAc/hexanes) to afford3-((6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate. ES/MS m/z: 350.1 [M+H].

Intermediate 632.6-chloro-8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine

6-chloro-8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) was prepared as follows: A microwave vial was chargedwith 8-bromo-6-chloro-imidazo[1,2-b]pyridazine (299 mg, 1.29 mmol, 1.2equiv), racemic2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(300 mg, 1.07 mmol, 1 equiv), cesium carbonate (698 mg, 2.14 mmol, 2equiv), and Pd(dppf)Cl₂CH₂Cl₂ (88 mg, 10 mol %). The solids weredissolved in dioxane (3 mL) and H₂O (1.5 mL), and the mixture wasdegassed with N2. The vial was sealed and heated to 120° C. for 4 h. Thereaction mixture was then cooled and filtered through celite, washingwith EtOAc. The filtrate was concentrated in vacuo, and the resultingresidue purified by silica gel chromatography (0-100% EtOAc/hexanes),affording6-chloro-8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 306.0 [M+H].

Intermediate 633.4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile

4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile(racemic mixture) was prepared in the manner described for Intermediate628, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-fluoro-4-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile.ES/MS m/z: 313.1 [M+H].

Intermediate 634.5-1(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile

5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile(racemic mixture) was prepared in the manner described for Intermediate628, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-fluoro-5-[(1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl]benzonitrile.ES/MS m/z: 313.1 [M+H].

Intermediate 635.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile(racemic mixture) was prepared in the manner described for Intermediate628, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith3-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 313.1 [M+H].

Intermediate 636.3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile(racemic mixture) was prepared in the manner described for Intermediate628, but replacing2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith2-fluoro-3-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 313.1 [M+H].

Intermediate 637.5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile.ES/MS m/z: 363.0 [M+H].

Intermediate 638.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 379.0 [M+H].

Intermediate 639.5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile

5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile(racemic mixture) was prepared in the manner described for Intermediate238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 379.0 [M+H].

Intermediate 640.4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrilewas prepared in the manner described for Intermediate 238, but replacing8-bromo-6-chloro-imidazo[1,2-b]pyridazine and4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and2-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile,respectively. ES/MS m/z: 331.1 [M+H].

Intermediate 641.6-chloro-8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 320.1 [M+H].

Intermediate 642.6-chloro-8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing8-bromo-6-chloro-imidazo[1,2-b]pyridazine and4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and2-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane,respectively. ES/MS m/z: 338.1 [M+H].

Intermediate 643.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith3,5-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 331.1 [M+H].

Intermediate 644.4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 238, but replacing8-bromo-6-chloro-imidazo[1,2-b]pyridazine and4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine and3,5-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile,respectively. ES/MS m/z: 349.1 [M+H].

Intermediate 645.4-((1S,2S)-2-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 238, but replacing8-bromo-6-chloro-imidazo[1,2-b]pyridazine and4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine and3,5-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile,respectively. ES/MS m/z: 332.0 [M+H].

Intermediate 646.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing8-bromo-6-chloro-imidazo[1,2-b]pyridazine and4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine and5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,respectively, and running the reaction at 90° C. ES/MS m/z: 393.1 [M+H].

Intermediate 647.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing8-bromo-6-chloro-imidazo[1,2-b]pyridazine and4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine and6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,respectively, and running the reaction at 80° C. ES/MS m/z: 393.1 [M+H].

Intermediate 648.6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing8-bromo-6-chloro-imidazo[1,2-b]pyridazine and4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith 8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine and5-chloro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine,respectively, and running the reaction at 80° C. ES/MS m/z: 306.0 [M+H].

Intermediate 649.5-chloro-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared as follows: To a solution of5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine (1.0 g, 5.29 mmol) in MeCN(25 mL) was added bromotrimethylsilane (3.49 mL, 26.5 mmol). The mixturewas stirred at rt for 1 h. The suspension was filtered, washing withMeCN, and the solids were then purified by silica gel chromatography(0-15% MeOH/DCM) to afford7-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyrimidine. ES/MS m/z: 233.0[M+H].

A microwave vial was charged with7-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyrimidine (117 mg, 0.50 mmol),potassium ((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)trifluoroborate(100 mg, 0.385 mmol), potassium carbonate (159 mg, 1.15 mmol), andPd(PPh₃)₄ (22 mg, 0.019 mmol). The solids were dissolved in toluene (2mL) and H₂O (0.4 mL), and the mixture was degassed with N₂. The vial wassealed and heated to 80° C. for 1 h. The reaction mixture was thencooled and filtered through celite, washing with EtOAc. The filtrate wasconcentrated in vacuo, and the resulting residue purified by silica gelchromatography (0-100% EtOAc/hexanes), affording5-chloro-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 307.0 [M+H].

Intermediate 650.5-chloro-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-chloro-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 649, but replacingpotassium ((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)trifluoroboratewith potassiumtrifluoro((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)borate. ES/MSm/z: 339.1 [M+H].

Intermediate 651.6-chloro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared as follows: A microwave vial was charged with8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine (50 mg, 0.214 mmol),potassiumtrifluoro((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)borate (48mg, 0.164 mmol), potassium carbonate (68 mg, 0.493 mmol), and Pd(PPh₃)₄(10 mg, 0.0082 mmol). The solids were dissolved in toluene (1 mL) andH₂O (0.2 mL), and the mixture was degassed with N₂. The vial was sealedand heated to 110° C. for 1 h. The reaction mixture was then cooled andfiltered through celite, washing with EtOAc. The filtrate wasconcentrated in vacuo, and the resulting residue purified by silica gelchromatography (0-100% EtOAc/hexanes), affording6-chloro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 339.0 [M+H].

Intermediate 652.4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile

4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile.ES/MS m/z: 417.1 [M+H].

Intermediate 653.6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 381.1 [M+H].

Intermediate 654.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 341.2 [M+H].

Intermediate 655.5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile

5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-2-fluoro-benzonitrile.ES/MS m/z: 417.1 [M+H].

Intermediate 656.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 399.1 [M+H].

Intermediate 657.6-(2,4-dimethoxypyrimidin-5-yl)-8-(2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 353.2 [M+H].

Intermediate 658.8-(3-(difluoromethyl)-3-methylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-(difluoromethyl)-3-methylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-(difluoromethyl)-3-methylazetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 377.2 [M+H].

Intermediate 659.8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 389.2 [M+H].

Intermediate 660.8-(3-cyclobutylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-cyclobutylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-cyclobutylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 367.2 [M+H].

Intermediate 661.5-(2,4-dimethoxypyrimidin-5-yl)-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-(2,4-dimethoxypyrimidin-5-yl)-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 400.1 [M+H].

Intermediate 662.8-(3-(difluoromethyl)azetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-(difluoromethyl)azetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-(difluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 363.1 [M+H].

Intermediate 663.8-(3-cyclopropylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-cyclopropylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-cyclopropylazetidin-1-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 353.2 [M+H].

Intermediate 664.8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 389.2 [M+H].

Intermediate 665.8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 375.2 [M+H].

Intermediate 666.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile.ES/MS m/z: 417.1 [M+H].

Intermediate 667.3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with3-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile.ES/MS m/z: 417.2 [M+H].

Intermediate 668.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 373.2 [M+H].

Intermediate 669.6-(2,4-dimethoxypyrimidin-5-yl)-8-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazine. ES/MSm/z: 342.1 [M+H].

Intermediate 670.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile.ES/MS m/z: 467.2 [M+H].

Intermediate 671.5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile.ES/MS m/z: 467.1 [M+H].

Intermediate 672.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 483.1 [M+H].

Intermediate 673.5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 483.1 [M+H].

Intermediate 674.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile.ES/MS m/z: 435.1 [M+H].

Intermediate 675.7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 411.1 [M+H].

Intermediate 676.5-(2,4-dimethoxypyrimidin-5-yl)-7-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine

5-(2,4-dimethoxypyrimidin-5-yl)-7-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 443.2 [M+H].

Intermediate 677.8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 424.2 [M+H].

Intermediate 678.8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 442.2 [M+H].

Intermediate 679.7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine

7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 392.2 [M+H].

Intermediate 680.5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine

5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-chloro-5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-a]pyrimidine.ES/MS m/z: 391.2 [M+H].

Intermediate 681.2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 449.2 [M+H].

Intermediate 682.8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-2-methylimidazo[1,2-b]pyrimidine

8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-2-methylimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoro-2-methylimidazo[1,2-b]pyridazine.ES/MS m/z: 423.2 [M+H].

Intermediate 683.8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-(1-trifluoromethyl)cyclopropyl(imidazo[1,2-b]pyrimidine

8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 499.2 [M+H].

Intermediate 684.8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyrimidine

8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 390.2 [M+H].

Intermediate 685.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile.ES/MS m/z: 435.1 [M+H].

Intermediate 686.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile.ES/MS m/z: 453.2 [M+H].

Intermediate 687.8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine

8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 392.2 [M+H].

Intermediate 688.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 443.2 [M+H].

Intermediate 689.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile.ES/MS m/z: 436.2 [M+H].

Intermediate 690.(R)-6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine

(R)-6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with(R)-6-chloro-8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 412.1 [M+H].

Intermediate 691.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 497.2 [M+H].

Intermediate 692.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 497.2 [M+H].

Intermediate 693.8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine

8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 525.2 [M+H].

Intermediate 694.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 400.2 [M+H].

Intermediate 695.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 542.2 [M+H].

Intermediate 696.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 506.2 [M+H].

Intermediate 697.1-(6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate

1-(6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate was prepared in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with1-(6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate. ES/MS m/z: 505.2 [M+H].

Intermediate 698.(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate

(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate was prepared in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate. ES/MS m/z: 486.2 [M+H].

Intermediate 699.3-((6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,2,2-trifluoroethyl)carbamate

3-((6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,2,2-trifluoroethyl)carbamate was prepared in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with3-((6-chloro-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate. ES/MS m/z: 454.2 [M+H].

Intermediate 700.8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine

8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 410.0 [M+H].

Intermediate 701.(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanol

(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanolwas prepared as follows: To a solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (150 mg,0.446 mmol) and (3-fluoroazetidin-3-yl)methanol (70 mg, 0.669 mmol) inNMP (2 mL) was added DIPEA (0.117 mL, 0.669 mmol), and the mixtureheated to 120° C. for 2 h. The mixture was then cooled, diluted withEtOAc, and washed with brine. Organics were dried over MgSO₄, filtered,and concentrated. The resulting residue was purified by silica gelchromatography (0-20% MeOH/DCM) to afford(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanol.ES/MS m/z: 361.2 [M+H].

Intermediate 702.5-(8-bromo-3-chloroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromo-3-chloroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a mixture of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (100mg, 0.290 mmol) and N-chlorosuccinimide (37 mg, 0.276 mmol) in DMF (1mL) was added DIPEA (0.076 mL, 0.435 mmol). The mixture was stirred 30°C. for 16 h, after which aqueous Na₂SO₃ and water were added. Themixture was stirred for 2 min, then filtered, rinsing with MeCN/water.Solids were dried in vacuo to afford5-(8-bromo-3-chloroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 341.9 [M+H]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.59 (s, 2H), 8.24(s, 1H), 8.11 (s, 1H), 7.97 (s, 1H).

Intermediate 703. 6-bromo-3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole

To a mixture of 6-bromo-3-chloro-1H-indazole (500 mg, 2.16 mmol) andcesium carbonate (704 mg, 2.16 mmol) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.358 mL, 2.48 mmol). The mixture was stirredat room temperature for 16 h, then diluted with EtOAc and washed twicewith brine. Combined organics were dried over MgSO₄, filtered, andconcentrated. The resulting residue was purified by silica gelchromatography (0-100% EtOAc/hexanes) to afford6-bromo-3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 7.62-7.54 (m, 2H), 7.40 (dd, J=8.6, 1.4 Hz, 1H), 4.84(q, J=8.3 Hz, 2H).

Intermediate 704. 6-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole

6-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole was prepared inthe manner described for Intermediate 703, but replacing6-bromo-3-chloro-1H-indazole with 6-bromo-4-chloro-1H-indazole. ¹H NMR(400 MHz, Chloroform-d) δ 8.13 (d, J=1.0 Hz, 1H), 7.53 (s, 1H), 7.36 (d,J=1.3 Hz, 1H), 4.90 (q, J=8.3 Hz, 2H).

Intermediate 705. 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylate

1,3-dioxoisoindolin-2-yl(1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylatewas prepared in the manner described for Steps 1 and 2 of Intermediate72, but replacing 5-bromo-2-chlorobenzonitrile with6-bromo-3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole, and running Step1 at 70° C. ES/MS m/z: 464.1 [M+H].

Intermediate 706.3-chloro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole

3-chloro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazolewas prepared as follows: To a solution of 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylate(385 mg, 0.830 mmol) and B2pin2 (632 mg, 2.49 mmol) in trifluorotoluene(4 mL) was added tert-butyl isonicotinate (0.071 mL, 0.415 mmol). Themixture was heated to 105° C. for 5 h, then cooled to room temperature,concentrated in vacuo, and the resulting residue purified by silica gelchromatography (0-100% EtOAc/hexanes) to afford3-chloro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 401.2 [M+H].

Intermediate 707. 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylate

1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylatewas prepared in the manner described for Steps 1 and 2 of Intermediate72, but replacing 5-bromo-2-chlorobenzonitrile with6-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole, and running Step1 at 70° C. ES/MS m/z: 464.1 [M+H].

Intermediate 708.4-chloro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole

4-chloro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazolewas prepared in the manner described for Intermediate 706, but replacing1,3-dioxoisoindolin-2-yl(1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylatewith 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylate.ES/MS m/z: 401.1 [M+H].

Intermediate 709. Potassiumtrifluoro((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)borate

Potassiumtrifluoro((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)boratewas prepared in the manner described for Intermediate 448, but replacing4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolanewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.¹H NMR (400 MHz, Acetone-d6) δ 7.92 (d, J=1.0 Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.26 (s, 1H), 6.87 (dd, J=8.4, 1.3 Hz, 1H), 5.21 (q, J=9.0 Hz,2H), 1.80-1.72 (m, 1H), 0.85 (td, J=7.4, 2.6 Hz, 1H), 0.52 (d, J=10.2Hz, 1H), 0.09-−0.02 (m, 1H). ¹⁹F NMR (376 MHz, Acetone-d6) δ −71.97 (t,J=9.0 Hz), −145.46 (d, J=77.9 Hz).

Intermediate 710.5-bromo-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidine

5-bromo-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidinewas prepared as follows: To a solution of5,7-dichloropyrazolo[1,5-a]pyrimidine (0.500 g, 2.66 mmol) in MeCN (13mL) was added bromotrimethylsilane (1.75 mL, 13.3 mmol). The mixture wasstirred at 60° C. for 3 h. The suspension was filtered, washing withMeCN, and the solids were dried under vacuum to afford ES/MS m/z: 276.0[M-FH].

A microwave vial was charged with 5,7-dibromopyrazolo[1,5-a]pyrimidine(354 mg, 1.28 mmol), potassiumtrifluoro((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)borate(295 mg, 0.852 mmol), cesium carbonate (833 mg, 2.56 mmol), andPd(PPh₃)₄ (49 mg, 0.043 mmol). The solids were dissolved in toluene (5mL) and H₂O (1 mL), and the mixture was degassed with N₂. The vial wassealed and heated to 100° C. for 5 h. The reaction mixture was thencooled and filtered through celite, washing with EtOAc. The filtrate wasconcentrated in vacuo, and the resulting residue purified by silica gelchromatography (0-100% EtOAc/hexanes), affording5-bromo-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 436.1 [M+H].

Intermediate 711.5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoropentanoic Acid

To a solution of ethyl 4,4-difluoro-5-hydroxy-pentanoate (500 mg, 2.74mmol) in THF (8 mL) and MeOH (4 mL) was added 2 M LiOH (4 mL, 8 mmol).The mixture was stirred overnight, allowing to warm to room temperature,then diluted with water and washed with EtOAc. Aqueous phase wasacidified using 2 M HCl, then extracted twice with EtOAc. Combinedorganics were dried over MgSO₄, filtered, and concentrated in vacuo toafford 4,4-difluoro-5-hydroxypentanoic acid, which was used withoutfurther purification.

To a solution of 4,4-difluoro-5-hydroxypentanoic acid (423 mg, 2.74mmol) in DMF (10 mL) at 0° C. was added NaH (231 mg, 6.04 mmol). Themixture was stirred for 20 min, after which8-bromo-6-chloro-imidazo[1,2-b]pyridazine (638 mg, 2.74 mmol) was added.The mixture was stirred for 2 h, allowing to warm to room temperature,then quenched with water and washed with EtOAc. Aqueous phase wasacidified using 2 M HCl, then extracted twice with EtOAc. Combinedorganics were dried over MgSO₄, filtered, and concentrated in vacuo toafford5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoropentanoicacid, which was used without further purification. ES/MS m/z: 305.5[M+H].

Intermediate 712.5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamide

5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamidewas prepared as follows: To a solution of5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoropentanoic acid(75 mg, 0.245 mmol) and HATU (112 mg, 0.294 mmol) in DMF (1 mL) wasadded isopropylamine (0.032 mL, 0.368 mmol), followed by DIPEA (0.128mL, 0.736 mmol). The mixture was stirred at room temperature for 16 h,then diluted with EtOAc and washed twice with brine. Combined organicswere then dried over MgSO₄, filtered, and concentrated in vacuo. Theresulting residue was purified by silica gel chromatography (0-100%EtOAc/hexanes) to afford5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamide.ES/MS m/z: 347.1 [M+H].

Intermediate 713.5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamide

5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamidewas prepared in the manner described for Intermediate 712, but replacingisopropylamine with 2,2,2-trifluoroethanamine. ES/MS m/z: 387.1 [M+H].

Intermediate 714.6-chloro-8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith3-chloro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,and running the reaction at 90° C. for 16 h. ES/MS m/z: 426.1 [M+H].

Intermediate 715.6-chloro-8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith4-chloro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,and running the reaction at ° C. for 16 h. ES/MS m/z: 426.0 [M+H].

Intermediate 716.5-((6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamide

5-((6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamidewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamide.ES/MS m/z: 451.2 [M+H].

Intermediate 717.5-((6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamide

5-((6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamidewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with5-((6-chloroimidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamide.ES/MS m/z: 491.1 [M+H].

Intermediate 718.8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as follows:6-chloro-8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(40 mg, 0.0938 mmol), cesium carbonate (61 mg, 0.118 mmol), andPd(dppf)Cl₂·CH₂Cl₂ (8 mg, 0.00938 mmol) were weighed into a microwavevial, and dioxane (0.4 mL) and water (0.2 mL) were added. The mixturewas degassed with N₂, then the vial was sealed and heated to 70° C. In aseparate vial, (2,4-dimethoxypyrimidin-5-yl)boronic acid (26 mg, 0.141mmol) was sonicated with dioxane (0.4 mL), and the mixture degassed withN₂. The suspension was then added dropwise to the heated solution ofaryl chloride, catalyst, and base, over the span of 45 min. The mixturewas stirred at 70° C. for an additional 30 min, then cooled to roomtemperature and filtered through celite, washing with DCM. The filtratewas concentrated in vacuo and purified by silica gel chromatography(0-20% MeOH/DCM) to afford8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 530.2 [M+H].

Intermediate 719.8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 718, but replacing6-chloro-8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewith6-chloro-8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 530.2 [M+H].

Intermediate 720. (S)-4,4-difluoropyrrolidin-3-ol Hydrochloride

(S)-4,4-difluoropyrrolidin-3-ol hydrochloride was prepared as follows:To a solution of tert-butyl(S)-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (5.20 g, 23.3 mmol,1 equiv) in DCM (20.0 mL) was gradually added 4.0 M HCl in dioxane (16.0mL, 64.0 mmol, 2.75 equiv). The reaction mixture was stirred at roomtemperature overnight. The solution was concentrated in vacuo to affordthe title compound in quantitative yield. 1H NMR (400 MHz, DMSO-d₆) δ10.21 (s, 2H), 6.68-6.51 (m, 1H), 4.36-4.24 (m, 1H), 3.71-3.12 (m, 4H).19F NMR (376 MHz, DMSO-d₆) δ −106.08-−107.51 (m), −120.49-−122.00 (m).

Intermediate 721.(S)-1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol

(S)-1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwas prepared as follows: A solution of8-bromo-6-chloroimidazo[1,2-b]pyridazine (3.64 g, 15.7 mmol, 1 equiv),(S)-4,4-difluoropyrrolidin-3-ol hydrochloride (2.50 g, 15.7 mmol, 1equiv) and DIPEA (6.55 mL, 37.6 mmol, 2.4 equiv) in ACN (50.0 mL) wasstirred at 85° C. for 7 h. The solution was diluted with water (150 mL)and extracted with EtOAc (3×100 mL). The organic fractions werecombined, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude material was loaded onto Celite and purified by silica gelchromatography (0-100% EtOAc in hexanes). ES/MS m/z: 275.0 [M+H].

Intermediate 722.(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol

(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwas prepared as follows: A 500 mL round-bottom flask was charged with(2,4-dimethoxypyrimidin-5-yl)boronic acid (2.54 g, 13.8 mmol, 1.2equiv), SPhos Pd G3 (350 mg, 0.449 mmol, 0.039 equiv) and potassiumcarbonate (3.18 g, 23.0 mmol, 2 equiv). To this was added(S)-1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(3.16 g, 11.5 mmol, 1 equiv) dissolved in 1,4 dioxane (60.0 mL). Thiswas followed by the addition of water (10.0 mL). The reaction mixturewas heated to 85° C. and stirred under Argon overnight. After cooling toroom temperature, the solution was diluted with water (150 mL) andextracted with EtOAc (2×150 mL). The organic fractions were combined,dried over Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was loaded onto Celite and purified by silica gelchromatography (0-100% EtOAc in hexanes) to afford the title compound.ES/MS m/z: 379.0 [M+H]. 1H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.12(d, J=1.2 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.28-6.23 (m, 2H), 4.54-4.06(m, 5H), 4.00-3.96 (m, 6H). 19F NMR (376 MHz, DMSO-d₆) δ −109.29-−111.10(m), −122.68 (d, J=233.0 Hz).

Intermediate 723.(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-3/1)oxy)-2-(trifluoromethyl)benzonitrile

(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethyl)benzonitrilewas prepared as follows: A microwave vial was charged with copper(I)iodide (41 mg, 0.215 mmol, 1.63 equiv),3,4,7,8-tetramethyl-1,10-phenanthroline (6 mg, 0.026 mmol, 0.2 equiv),cesium carbonate (65 mg, 0.198 mmol, 1.5 equiv),(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(50 mg, 0.132 mmol, 1 equiv) and 4-iodo-2-(trifluoromethyl)benzonitrile(43 mg, 0.145 mmol, 1.1 equiv). The vial was sealed and toluene (3.0 mL)was added under an Argon atmosphere. The reaction mixture was graduallyheated to 120° C. and stirred overnight.

After cooling to room temperature, the mixture was diluted with EtOAcand filtered through a pad of Celite. The filtrate was concentratedunder reduced pressure and the crude material was purified by silica gelchromatography (0-100% EtOAc in hexanes) to afford the title compound.ES/MS m/z: 548.0 [M+H].

Intermediate 724.(S)-1-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ol

(S)-1-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-olwas prepared as follows: A solution of5,7-dichloropyrazolo[1,5-a]pyrimidine (236 mg, 1.25 mmol, 1 equiv),(S)-4,4-difluoropyrrolidin-3-ol hydrochloride (200 mg, 1.25 mmol, 1equiv) and DIPEA (0.52 mL, 3.01 mmol, 2.4 equiv) in ACN (10.0 mL) wasstirred at 85° C. for 3 h and 15 min. The reaction mixture was dilutedwith water, the resulting solids filtered, washed with water and driedto afford the title compound. ES/MS m/z: 275.0 [M+H]. ¹H NMR (400 MHz,DMSO-d₆) δ 8.10 (d, J=2.3 Hz, 1H), 6.42 (d, J=2.3 Hz, 1H), 6.30 (d,J=5.2 Hz, 1H), 6.12 (s, 1H), 4.53-3.90 (m, 5H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −110.37 (d, J=232.8 Hz), −122.92 (d, J=232.9 Hz).

Intermediate 725.(S)-1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ol

(S)-1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-olwas prepared as follows: A solution of(S)-1-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ol(263 mg, 0.958 mmol, 1 equiv), Pd(dppf)Cl₂CH₂Cl₂ (78 mg, 0.096 mmol, 0.1equiv) and cesium carbonate (624 mg, 1.92 mmol, 2 equiv) in 1,4 dioxane(6.0 mL) and water (0.80 mL) was gradually heated to 70° C. In aseparate vial, (2,4-dimethoxypyrimidin-5-yl)boronic acid (238 mg, 1.29mmol, 1.35 equiv) was sonicated in 1,4 dioxane (6.0 mL). The suspensionwas added gradually to the reaction mixture over a period of 40 min. Thesolution was stirred at 70° C. for an additional 2 h prior to dilutingwith EtOAc and filtering through a pad of Celite. The filtrate wasconcentrated under reduced pressure and the crude material was purifiedby silica gel chromatography (0-100% EtOAc in hexanes) to afford thetitle compound. ES/MS m/z: 379.1 [M+H].

Intermediate 726.(S)-1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate

(S)-1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate was prepared as follows: To a solution of(S)-1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ol(30 mg, 0.079 mmol, 1 equiv) in DCM (2.0 mL) was added DIPEA (0.14 mL,0.793 mmol, 10 equiv), followed by 2-isocyanatopropane (0.04 mL, 0.396mmol, 5 equiv). The reaction mixture was heated to 60° C. and stirredovernight. The solution was diluted with water and extracted with EtOAc(2×). Organic fractions were dried over MgSO₄ and concentrated prior topurification by silica gel chromatography (0-100% EtOAc in hexanes) toafford the title compound. ES/MS m/z: 464.1 [M+H].

Intermediate 727. 6-bromo-4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazole

6-bromo-4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazole was prepared inthe manner described for Intermediate 703, but replacing6-bromo-3-chloro-1H-indazole with 6-bromo-4-methyl-1H-indazole. ES/MSm/z: 293.1 [M+H]. ¹H NMR (400 MHz, Chloroform-d) δ 8.06 (d, J=1.0 Hz,1H), 7.45 (s, 1H), 7.14 (t, J=1.2 Hz, 1H), 4.89 (q, J=8.4 Hz, 2H), 2.58(s, 3H).

Intermediate 728. 5,7-dibromo-3-fluoropyrazolo[1,5-a]pyrimidine

5,7-dibromo-3-fluoropyrazolo[1,5-a]pyrimidine was prepared as follows:To a mixture of 5,7-dibromopyrazolo[1,5-a]pyrimidine (0.800 g, 2.89mmol) in MeCN (15 mL) was added SelectFluor (1.126 g, 3.18 mmol). Themixture was stirred at 60° C. for 2.5 h, after which additionalSelectFluor (512 mg, 1.44 mmol) was added. The mixture was stirred at60° C. for 8 h, after which it was cooled to rt, concentrated in vacuo,and the residue purified by RP-HPLC (10-90% MeCN/H₂O with TFA modifier,Gemini column). NaHCO₃sat. solution was added to the purified residue,and the aqueous phase extracted twice with DCM. The combined organicswere dried over MgSO₄, filtered, and concentrated in vacuo to afford5,7-dibromo-3-fluoropyrazolo[1,5-a]pyrimidine. ES/MS m/z: 293.9 [M+H].¹H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J=3.7 Hz, 1H), 7.27 (s, 1H).

Intermediate 729.((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)trifluoro-14-borane,Potassium Salt

((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)trifluoro-14-borane,potassium salt was prepared in the manner described for Intermediate448, but replacing4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolanewith2-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Intermediate 730. 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylate

1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylatewas prepared in the manner described for Steps 1 and 2 of Intermediate72, but replacing 5-bromo-2-chlorobenzonitrile with6-bromo-4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazole, and running Step1 at 70° C. ES/MS m/z: 444.1 [M+H].

Intermediate 731.4-methyl-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole

4-methyl-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazolewas prepared in the manner described for Intermediate 706, but replacing1,3-dioxoisoindolin-2-yl(1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylatewith 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropane-1-carboxylate.ES/MS m/z: 381.3 [M+H].

Intermediate 732. Potassiumtrifluoro((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)borate

Potassiumtrifluoro((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)boratewas prepared in the manner described for Intermediate 448, but replacing4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolanewith6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.1H NMR (400 MHz, Acetone-d6) δ 6.82-6.62 (m, 3H), 4.60 (q, J=9.3 Hz,2H), 1.68-1.59 (m, 1H), 1.53 (dt, J=4.9, 3.4 Hz, 4H), 0.78 (td, J=7.3,2.5 Hz, 1H), 0.42 (d, J=10.2 Hz, 1H), −0.07 (ddd, J=7.1, 5.7, 3.0 Hz,1H). 19F NMR (376 MHz, Acetone-d6) δ −71.03 (t, J=9.3 Hz), −145.57 (d,J=75.9 Hz).

Intermediate 733.6′-((1S,2S)-2-(5-bromopyrazolo[1,5-a]pyrimidin-7-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(5-bromopyrazolo[1,5-a]pyrimidin-7-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 710, but replacingpotassiumtrifluoro((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)boratewith potassiumtrifluoro((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)borate.ES/MS m/z: 477.1 [M+H].

Intermediate 734.6-chloro-8-((1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith4-methyl-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,and running the reaction at 100° C. for 16 h. ES/MS m/z: 406.1 [M+H].

Intermediate 735.5-bromo-3-fluoro-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-1/1)cyclopropyl)pyrazolo[1,5-a]pyrimidine

5-bromo-3-fluoro-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidinewas prepared in the manner described for Step 2 of Intermediate 710, butreplacing 5,7-dibromopyrazolo[1,5-a]pyrimidine with5,7-dibromo-3-fluoropyrazolo[1,5-a]pyrimidine. ES/MS m/z: 454.0 [M+H].

Intermediate 736. 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.5 g, 12.6 mmol, 1equiv) in ACN (60 mL) was addedN-Fluoro-N′-chloromethyltriethylenediamine (6.71 g, 18.9 mmol, 1.5equiv). The reaction mixture was heated to 90 C. After 2.5 hours, thereaction mixture was filtered, and the filtrate was concentrated.Purification was accomplished by SiO₂ chromatography (0-100% EtOAc/Hex),affording 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine. ES/MS m/z: 216.00[M+H].

Intermediate 737.6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (0.59 g,2.74 mmol, 1 equiv) in DMF (4 mL) was added potassium carbonate (1138mg, 8.23 mmol, 3 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (955 mg, 4.12 mmol, 1.5 equiv). The reactionmixture was heated to 80° C. After 1 hour, the reaction mixture wasdiluted with brine (50 mL) and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-50% EtOAc/Hex),affording6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine. ES/MSm/z: 298.00 [M+H].

Intermediate 738.8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

Step 1: To a stirred solution of 6-chloropyridazin-3-amine (200 g, 1.55mol, 1 equiv) and (2,4-dimethoxypyrimidin-5-yl)boronic acid (312.4 g,1.69 mol, 1.1 equiv) in 1,4-dioxane (4 L) and water (2 L) was addedpotassium carbonate (427.90 g, 3.1 mol, 2 equiv) and degassed forminutes using Argon. PdCl₂(dppf)-CH₂Cl₂ (25.3 g, 2 mol %) was added tothe reaction mixture, which was degassed for 10 minutes using Argon. Thereaction mixture was heated to ° C. After 2 hours, the reaction mixturewas cooled to 50° C., filtered over celite with 1,4-dioxane washings,and concentrated. The resulting residue was diluted with water (1.6 L),stirred for 30 minutes, and filtered. The remaining solids weretriturated with IPA (1 L) and dried under vacuum to afford6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine. This material was usedin the next step without further purification.

Step 2: To a stirred suspension of6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (25 g, 0.107 mol, 1equiv) in MeOH (250 mL) was added sodium acetate (7.04 g, 0.085 mol, 0.8equiv) and acetic acid (1.72 g, 0.028 mol, 0.26 equiv). To thisresulting heterogeneous reaction mixture was added1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (18.4 g, 0.064 mol, 0.6equiv) portionwise. After 2 hours, the reaction mixture was quenchedwith a 38% aqueous solution of NaHSO₃ and concentrated. The resultingresidue was diluted with water (250 mL) and filtered. The remainingsolids were purified by SiO₂ chromatography (2-3% MeOH/CH₂Cl₂),affording 4-bromo-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine.

Step 3: To a stirred suspension of4-bromo-6-(2,4-dimethoxypyrimidin-5-yl)pyridazin-3-amine (80 g, 0.256mol, 1 equiv) in MeOH (2.4 L) was added 55% aqueous 2-chloroacetaldehyde(183 g, 1.28 mol, 5 equiv). The reaction mixture was heated to 60° C.After 24 hours, the heterogeneous reaction mixture was filtered. Theremaining solids were purified by SiO₂ chromatography (2-3%MeOH/CH₂Cl₂), affording8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.

Intermediate 739.6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (1 g, 5.05 mmol, 1equiv) in DMF (20 mL) was added potassium carbonate (2094 mg, 15.1 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.09 mL,7.57 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 2hours, the reaction mixture was diluted with brine (50 mL) and extractedwith 80% EtOAc/Hex (2×100 mL). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated. Purification was accomplishedby SiO₂ chromatography (0-100% EtOAc/Hex), affording6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine. ¹H NMR (400MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 5.52 (q, J=9.1Hz, 2H). ES/MS m/z: 280.00 [M+H].

Intermediate 740.6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

To a solution of 6-bromo-1H-pyrazolo[3,4-b]pyridine (400 mg, 2.02 mmol,1 equiv) in DMF (6 mL) was added potassium carbonate (838 mg, 6.06 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.44 mL,3.03 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 1hour, the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine. ¹H NMR (400MHz, Chloroform-d) δ 8.10 (s, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.37 (d,J=8.3 Hz, 1H), 5.08 (q, J=8.3 Hz, 2H). ES/MS m/z: 280.00 [M+H].

Intermediate 741.6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (4000 mg, 20.2 mmol,1 equiv) in DMF (30 mL) was added potassium carbonate (8375 mg, 60.6mmol, 3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.37mL, 30.3 mmol, 1.5 equiv). The reaction mixture was heated to 80° C.After 1 hour, the reaction mixture was diluted with water (30 mL) andextracted with 50% EtOAc/Hex (3×50 mL). The combined organic layers wereconcentrated and purified by SiO₂ chromatography, affording6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine. ¹H NMR (400MHz, DMSO-d₆) δ 8.74 (bs, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.50 (s, 1H),5.51 (q, J=9.1 Hz, 2H). ES/MS m/z: 282.00 [M+H].

Intermediate 742.6-bromo-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazole

To a solution of 6-bromo-3-(trifluoromethyl)-1H-indazole (1000 mg, 3.77mmol, 1 equiv) in DMF (10 mL) was added potassium carbonate (1043 mg,7.55 mmol, 2 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(0.82 mL, 5.66 mmol, 1.5 equiv). The reaction mixture was heated to 80°C. After 1 hour, the reaction mixture was directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording6-bromo-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazole. ¹H NMR(400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.66-7.55 (m,1H), 5.67 (q, J=9.1 Hz, 2H).

Intermediate 743.6-chloro-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 6-chloro-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine(1000 mg, 4.51 mmol, 1 equiv) in DMF (12 mL) was added potassiumcarbonate (1871 mg, 13.5 mmol, 3 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.78 mL, 5.42 mmol, 1.1 equiv). The reactionmixture was heated to 80° C. After 30 minutes, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording6-chloro-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.32 (s, 1H), 5.70 (q, J=9.0Hz, 2H). ES/MS m/z: 304.00 [M+H].

Intermediate 744.6-bromo-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole

To a solution of 6-bromo-2-(trifluoromethyl)-1H-benzo[d]imidazole (1500mg, 5.66 mmol, 1 equiv) in DMF (12 mL) was added potassium carbonate(1564 mg, 11.3 mmol, 2 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.22 mL, 8.49 mmol, 1.5 equiv). The reactionmixture was heated to 80° C. After 1 hour, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording6-bromo-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole.¹H NMR (400 MHz, DMSO-d₆) δ 8.30 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.62(dd, J=8.7, 1.8 Hz, 1H), 5.52 (q, J=8.9 Hz, 2H). ES/MS m/z: 347.00[M+H].

Intermediates 745 and 746.6-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazoleand5-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazoleand

To a solution of 6-bromo-2-(difluoromethyl)-1H-benzo[d]imidazole (1000mg, 4.05 mmol, 1 equiv) in DMF (12 mL) was added potassium carbonate(1119 mg, 8.10 mmol, 2 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.88 mL, 6.07 mmol, 1.5 equiv). The reactionmixture was heated to 80° C. After 1 hour, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording amixture of6-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazoleand5-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole.This mixture was separated by RP-HPLC (10-100% MeCN/H₂O with TFAmodifier). Characterization data for Intermediate 7456-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole:¹H NMR (400 MHz, DMSO-d₆) δ 8.18 (bs, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.54(dd, J=8.7, 1.8 Hz, 1H), 7.46 (t, J=51.4 Hz, 1H), 5.49 (q, J=8.8 Hz,2H). Characterization data for Intermediate 7465-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole:¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=1.9 Hz, 1H), 7.83 (d, J=8.8 Hz,1H), 7.65 (dd, J=8.8, 1.9 Hz, 1H), 7.47 (t, J=51.4 Hz, 1H), 5.51 (q,J=8.7 Hz, 2H).

Intermediate 747.6-chloro-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine

Step 1: A solution of 6-chloropyridine-3,4-diamine (1000 mg, 6.97 mmol,1 equiv) in TFA (14 mL) was heated to 70° C. After 16 hours, thereaction mixture was concentrated. Triethylamine (10 mL) was added, andafter an additional 24 hours at 70° C., the reaction mixture was againconcentrated. Purification was accomplished by SiO₂ chromatography(0-20% MeOH/CH₂Cl₂), affording6-chloro-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine. ES/MS m/z:222.00 [M+H].

Step 2: To a solution of6-chloro-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (1000 mg, 4.51mmol, 1 equiv) in DMF (15 mL) was added potassium carbonate (1871 mg,13.5 mmol, 3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate(1.95 mL, 13.5 mmol, 3 equiv). The reaction mixture was heated to 80° C.After 24 hours, the reaction mixture was diluted with brine (50 mL) andextracted with EtOAc (3×50 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated. Purification was accomplished bySiO₂ chromatography (0-100% EtOAc/Hex), affording6-chloro-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.24 (s, 1H), 5.54 (q, J=8.8Hz, 2H). ES/MS m/z: 304.10 [M+H].

Intermediate 748. 2-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)pyridine

To a solution of 2-bromo-5-chloropyridin-4-ol (1000 mg, 4.8 mmol, 1equiv) in DMF (15 mL) was added potassium carbonate (1989 mg, 14.4 mmol,3 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.04 mL,7.2 mmol, 1.5 equiv). The reaction mixture was heated to ° C. After 2hours, the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording2-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)pyridine. ¹H NMR (400 MHz,Chloroform-d) δ 8.30 (s, 1H), 7.01 (s, 1H), 4.48 (q, J=7.6 Hz, 2H).ES/MS m/z: 291.90 [M+H].

Intermediate 749.2-bromo-5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridine

To a solution of 2-bromo-5-chloropyridin-4-ol (150 mg, 0.72 mmol, 1equiv) in DMF (1.5 mL) was added potassium carbonate (298 mg, 2.16 mmol,3 equiv) and 2-(bromomethyl)-1,1-difluorocyclopropane (0.16 mL, 1.08mmol, 1.5 equiv). The reaction mixture was heated to ° C. After 90minutes, the reaction mixture was directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording2-bromo-5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridine. ¹H NMR(400 MHz, Chloroform-d) δ 8.23 (s, 1H), 6.98 (s, 1H), 4.26-4.06 (m, 2H),2.21-2.08 (m, 1H), 1.75-1.62 (m, 1H), 1.44-1.29 (m, 1H). ES/MS m/z:299.90 [M+H].

Intermediates 750 and 751. 7-bromo-2-(2,2,2-trifluoroethoxy)quinolineand 7-bromo-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one

To a solution of 7-bromoquinolin-2(1H)-one (500 mg, 2.23 mmol, 1 equiv)in DMF (6 mL) was added potassium carbonate (925 mg, 6.69 mmol, 3 equiv)and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.83 mL, 3.35 mmol,1.5 equiv). The reaction mixture was heated to ° C. After 1 hour, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording 7-bromo-2-(2,2,2-trifluoroethoxy)quinoline and7-bromo-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one. Characterizationdata for 7-bromo-2-(2,2,2-trifluoroethoxy)quinoline: ¹H NMR (400 MHz,Chloroform-d) δ 8.07-8.00 (m, 2H), 7.62 (d, J=8.6 Hz, 1H), 7.56-7.48 (m,1H), 7.02 (d, J=8.9 Hz, 1H), 4.91 (q, J=8.6 Hz, 2H). Characterizationdata for 7-bromo-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one: ¹H NMR (400MHz, Chloroform-d) δ 7.67 (d, J=9.6 Hz, 1H), 7.54 (s, 1H), 7.46-7.37 (m,2H), 6.73 (d, J=9.6 Hz, 1H), 5.07-4.84 (m, 2H).

Intermediate 752. 6-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole

To a solution of 6-bromo-4-fluoro-1H-indazole (1 g, 4.65 mmol, 1 equiv)in DMF (12 mL) was added potassium carbonate (1285 mg, 9.30 mmol, 2equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.01 mL, 6.98mmol, 1.5 equiv). The reaction mixture was heated to ° C. After 1 hour,the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 8.12 (s, 1H), 7.43 (s, 1H), 7.05 (d, J=9.0 Hz, 1H), 4.91(q, J=8.3 Hz, 2H). ES/MS m/z: 297.00 [M+H].

Intermediate 753. 6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole

To a solution of 6-bromo-5-fluoro-1H-indazole (1 g, 4.65 mmol, 1 equiv)in DMF (12 mL) was added potassium carbonate (1285 mg, 9.30 mmol, 2equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.01 mL, 6.98mmol, 1.5 equiv). The reaction mixture was heated to ° C. After 1 hour,the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 8.04 (d, J=1.0 Hz, 1H), 7.69 (d, J=5.2 Hz, 1H), 7.46 (d,J=7.9 Hz, 1H), 4.91 (q, J=8.4 Hz, 2H). ES/MS m/z: 297.00 [M+H].

Intermediate 754. 6-bromo-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole

To a solution of 6-bromo-7-fluoro-1H-indazole (1 g, 4.65 mmol, 1 equiv)in DMF (12 mL) was added potassium carbonate (1285 mg, 9.30 mmol, 2equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.01 mL, 6.98mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 1hour, the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-bromo-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 8.07 (d, J=2.3 Hz, 1H), 7.42-7.38 (m, 1H), 7.35-7.29 (m,1H), 5.08 (q, J=8.1 Hz, 2H). ES/MS m/z: 297.00 [M+H].

Intermediate 755.6-bromo-4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazole

Step 1: To a solution of 6-bromo-4-fluoro-1H-indazole (1 g, 4.65 mmol, 1equiv) in DMF (12 mL) was added potassium carbonate (1285 mg, 9.30 mmol,2 equiv) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.01 mL,6.98 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. After 1hour, the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 8.12 (s, 1H), 7.43 (s, 1H), 7.05 (d, J=9.0 Hz, 1H), 4.91(q, J=8.3 Hz, 2H). ES/MS m/z: 297.00 [M+H].

Step 2: To a solution of6-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole (2.32 g, 7.81mmol, 1 equiv) in 20:1 MeCN/AcOH (50 mL) was added1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (5534 mg, 15.6 mmol, 2 equiv). The reactionmixture was heated to 70° C. After 14 hours, the reaction mixture washeated to 100° C. After an additional 4 hours, the reaction mixture wascooled to room temperature and concentrated. Purification wasaccomplished by SiO₂ chromatography (0-30% EtOAc/Hex), affording6-bromo-4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400MHz, DMSO-d₆) δ 8.50 (d, J=2.1 Hz, 1H), 7.44 (dd, J=8.8, 4.0 Hz, 1H),5.46 (q, J=8.9 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −70.90 (td, J=8.8,6.4 Hz), −121.45 (dd, J=21.9, 8.8 Hz), −132.17-−132.36 (m).

Intermediate 756. 6-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridine

Step 1: To a solution of (5-bromopyridin-2-yl)methanamine (1000 mg, 5.35mmol, 1 equiv), 3,3,3-trifluoropropanoic acid (822 mg, 6.42 mmol, 1.2equiv), and HATU (3049 mg, 8.02 mmol, 1.5 equiv) in DMF (10 mL) wasadded DIPEA (2.38 mL, 13.4 mmol, 2.5 equiv). After 3 hours, the reactionmixture was quenched with H₂O (10 mL) and extracted with EtOAc (3×10mL). The combined organic layers were concentrated and purified by SiO₂chromatography (0-100% EtOAc/Hex), affordingN-((5-bromopyridin-2-yl)methyl)-3,3,3-trifluoropropanamide. ¹H NMR (400MHz, DMSO-d₆) δ 8.87 (t, J=5.9 Hz, 1H), 8.64 (d, J=2.4 Hz, 1H), 8.04(dd, J=8.4, 2.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.37 (d, J=5.9 Hz, 2H),3.36 (q, J=11.4 Hz, 2H). ES/MS m/z: 297.00 [M+H].

Step 2: To a suspension ofN-((5-bromopyridin-2-yl)methyl)-3,3,3-trifluoropropanamide (150 mg, 0.51mmol, 1 equiv) in Toluene (2 mL) was added phosphoryl trichloride (0.19mL, 2.02 mmol, 4 equiv). The reaction mixture was heated to 90° C. After6 hours, the reaction mixture was cooled to 0° C. and quenched withsaturated aqueous NaHCO₃ (3 mL). The reaction mixture was directlypurified by SiO₂ chromatography (0-30% MeOH/CH₂Cl₂), affording6-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridine. ¹H NMR (400 MHz,DMSO-d₆) δ 8.85 (s, 1H), 7.63 (d, J=9.6 Hz, 1H), 7.56 (s, 1H), 6.97 (d,J=9.6 Hz, 1H), 4.34 (q, J=10.8 Hz, 2H). ES/MS m/z: 279.00 [M+H].

Intermediate 757.6-bromo-3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridine

Step 1: To a solution of1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethan-1-amine hydrochloride (1000mg, 3.92 mmol, 1 equiv), 3,3,3-trifluoropropanoic acid (527 mg, 4.12mmol, 1.05 equiv), and HATU (2236 mg, 5.88 mmol, 1.5 equiv) in DMF (10mL) was added DIPEA (1.75 mL, 9.80 mmol, 2.5 equiv). After 3 hours, thereaction mixture was quenched with H₂O (10 mL) and extracted with EtOAc(3×10 mL). The combined organic layers were concentrated and purified bySiO₂ chromatography (0-100% EtOAc/Hex), affordingN-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3,3,3-trifluoropropanamide.¹H NMR (400 MHz, DMSO-d₆) δ 9.53 (d, J=9.3 Hz, 1H), 8.80 (d, J=2.4 Hz,1H), 8.21 (dd, J=8.4, 2.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 6.01 (p,J=8.3 Hz, 1H), 3.61-3.44 (m, 2H). ES/MS m/z: 367.00 [M+H].

Step 2: To a suspension ofN-(1-(5-bromopyridin-2-yl)-2,2,2-trifluoroethyl)-3,3,3-trifluoropropanamide(200 mg, 0.55 mmol, 1 equiv) in Toluene (2 mL) was added phosphoryltrichloride (0.26 mL, 2.74 mmol, 5 equiv). The reaction mixture washeated to 90° C. After 30 hours, the reaction mixture was cooled to 0°C. and quenched with saturated aqueous NaHCO₃ (3 mL). The reactionmixture was directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording6-bromo-3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 7.72-7.64 (m, 1H), 7.37-7.28(m, 1H), 4.41 (q, J=10.7 Hz, 2H). ES/MS m/z: 347.00 [M+H].

Intermediate 758. 7-chloro-3-(trifluoromethyl)imidazo[1,5-a]pyridine

To a cooled (−10° C.) solution of (4-chloropyridin-2-yl)methanamine(1000 mg, 7.01 mmol, 1 equiv) and pyridine (2.43 mL, 30.2 mmol, 4.3equiv) in CH₂Cl₂ (10 mL) was added a solution of trifluoroaceticanhydride (3.12 mL, 22.4 mmol, 3.2 equiv) in CH₂Cl₂ (14 mL) dropwise.After 23 hours, the reaction mixture was warmed to room temperature andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording7-chloro-3-(trifluoromethyl)imidazo[1,5-a]pyridine. ¹H NMR (400 MHz,DMSO-d₆) δ 8.45 (d, J=7.5 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.61 (s, 1H),7.04 (dd, J=7.5, 2.1 Hz, 1H).

Intermediate 759.6-bromo-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine

To a solution of 6-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine (200mg, 0.76 mmol, 1 equiv) in DMSO (6 mL) was added1,1,1-trifluoro-2-iodoethane (0.223 mL, 2.26 mmol, 3 equiv), potassiumcarbonate (209 mg, 1.51 mmol, 2 equiv), and Ir(ppy)₃ (25 mg, 5 mol %).The reaction mixture was stirred at room temperature under blue LEDirradiation. After 48 hours, the reaction mixture was directly purifiedby SiO₂ chromatography (0-100% EtOAc/Hex), affording6-bromo-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine.¹H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.63 (d, J=9.7 Hz, 1H),7.52 (d, J=9.7 Hz, 1H), 4.08 (q, J=9.5 Hz, 2H). ¹⁹F NMR (376 MHz,DMSO-d₆) δ −61.86, −62.31 (t, J=10.2 Hz). ES/MS m/z: 347.00 [M+H].

Intermediate 760.6-chloro-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

To a solution of 6-chloro-7-fluoro-1H-pyrazolo[4,3-c]pyridine (1000 mg,5.83 mmol, 1 equiv) in DMF (10 mL) was added potassium carbonate (2417mg, 17.5 mmol, 3 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (1.01 mL, 6.99 mmol, 1.2 equiv). The reactionmixture was heated to 80° C. After 1 hour, the reaction mixture wasdiluted with water (50 mL) and extracted with 50% EtOAc/Hex (3×50 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording6-chloro-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.60 (d, J=2.3 Hz, 1H), 5.49(q, J=8.9 Hz, 2H). ES/MS m/z: 254.00 [M+H].

Intermediate 761.7-bromo-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

Step 1: To a cooled (0° C.) solution of5-(trifluoromethyl)pyrrolidin-2-one (835 mg, mmol, 2 equiv) in DMF (5mL) was added 60% sodium hydride (209 mg, 5.45 mmol, 2 equiv). After 5minutes, 4-bromo-2-fluoro-1-nitrobenzene (600 mg, 2.73 mmol, 1 equiv)was added. After stirring for 1 hour at 0° C. and an additional 1 hourat room temperature, the reaction mixture was quenched with saturatedaqueous NaHCO₃ (5 mL) and directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording1-(5-bromo-2-nitrophenyl)-5-(trifluoromethyl)pyrrolidin-2-one. ¹H NMR(400 MHz, DMSO-d₆, diagnostic peaks) δ 8.12 (d, J=2.1 Hz, 1H), 7.98 (d,J=8.7 Hz, 1H), 7.78 (dd, J=8.7, 2.1 Hz, 1H), 5.47-5.34 (m, 1H).

Step 2: To a solution of1-(5-bromo-2-nitrophenyl)-5-(trifluoromethyl)pyrrolidin-2-one (1240 mg,3.51 mmol, 1 equiv) in 3:1 EtOH/H₂O (8 mL) was added iron (981 mg, 17.6mmol, 5 equiv) and ammonium chloride (564 mg, 10.5 mmol, 3 equiv). Thereaction mixture was heated to 80° C. After 3 hours, the reactionmixture was filtered with EtOAc washings (10 mL). The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated to afford1-(2-amino-5-bromophenyl)-5-(trifluoromethyl)pyrrolidin-2-one. Thismaterial was used in the next step without purification. ES/MS m/z:323.00 [M+H].

Step 3: A solution of1-(2-amino-5-bromophenyl)-5-(trifluoromethyl)pyrrolidin-2-one (1135 mg)in AcOH (10 mL) was heated to 110° C. After 3 hours, the reactionmixture was cooled to room temperature and concentrated. The resultingresidue was dissolved in EtOAc (20 mL) and washed with saturated aqueousNaHCO₃ (20 mL). The layers were separated, and the organic layer wasconcentrated and purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording7-bromo-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole.¹H NMR (400 MHz, DMSO-d₆, diagnostic peaks) δ 7.70 (bs, 1H), 7.57 (d,J=8.6 Hz, 1H), 7.37 (dd, J=8.6, 2.0 Hz, 1H), 5.60-5.47 (m, 1H). ES/MSm/z: 307.00 [M+H].

Intermediate 762. 2-chloro-4-(2-(trifluoromethyl)phenyl)pyridine

A solution of 2-chloro-4-iodopyridine (200 mg, 0.84 mmol, 1 equiv),(2-(trifluoromethyl)phenyl)boronic acid (175 mg, 0.92 mmol, 1.1 equiv),potassium carbonate (346 mg, 2.51 mmol, 3 equiv), and (dppf)PdCl₂—CH₂Cl₂(15 mg, 2.5 mol %) in 4:1 THF/H₂O (2 mL) was heated to 80° C. After 1hour, the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording2-chloro-4-(2-(trifluoromethyl)phenyl)pyridine. ¹H NMR (400 MHz,DMSO-d₆) δ 8.50 (d, J=5.1 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.82-7.76 (m,1H), 7.75-7.66 (m, 1H), 7.54 (s, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.43-7.40(m, 1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −55.90. ES/MS m/z: 258.10 [M-FH].

Intermediate 763. 2-chloro-4-(2,4-difluorophenyl)pyridine

A solution of 2-chloro-4-iodopyridine (200 mg, 0.84 mmol, 1 equiv),(2,4-difluorophenyl)boronic acid (145 mg, 0.92 mmol, 1.1 equiv),potassium carbonate (346 mg, 2.51 mmol, 3 equiv), and (dppf)PdCl₂—CH₂Cl₂(15 mg, 2.5 mol %) in 4:1 THF/H₂O (2 mL) was heated to 80° C. After 1hour, the reaction mixture was directly purified by SiO₂ chromatography(0-100% EtOAc/Hex), affording 2-chloro-4-(2,4-difluorophenyl)pyridine.¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (d, J=5.2 Hz, 1H), 7.82-7.74 (m, 1H),7.73-7.70 (m, 1H), 7.64-7.60 (m, 1H), 7.54-7.43 (m, 1H), 7.33-7.22 (m,1H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −108.24-−108.36 (m), −112.98-−113.13(m). ES/MS m/z: 226.00 [M+H].

Intermediate 764. 7-chloro-5-(2,2,2-trifluoroethoxy)quinoline

To a solution of 7-chloroquinolin-5-ol (500 mg, 2.78 mmol, 1 equiv) inDMF (6 mL) was added potassium carbonate (1154 mg, 8.35 mmol, 3 equiv)and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.602 mL, 4.18 mmol,1.5 equiv). The reaction mixture was heated to 80° C. After 1 hour, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording 7-chloro-5-(2,2,2-trifluoroethoxy)quinoline. ¹HNMR (400 MHz, DMSO-d₆) δ 9.00-8.94 (m, 1H), 8.50-8.43 (m, 1H), 7.80-7.73(m, 1H), 7.61 (dd, J=8.5, 4.3 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 5.08 (q,J=8.8 Hz, 2H). ES/MS m/z: 262.10 [M+H].

Intermediate 765. Racemic Potassium(3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl) trifluoroborate

Step 1: To a solution of(E)-2-(3,4-difluorostyryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1000mg, 3.76 mmol, 1 equiv) in MeOH (15 mL) was added potassium hydrogendifluoride (1761 mg, 22.5 mmol, 6 equiv) and heated to 80° C. After 8hours, the reaction mixture was cooled to room temperature andconcentrated. The resulting residue was triturated with 50% Et20 inheptane (10 mL). After 10 minutes, the precipitate was collected byfiltration, rinsing with Et2O (10 mL), and dried under reduced pressure,affording crude potassium (E)-(3,4-difluorostyryl)trifluoroborate. Thismaterial was used in the next step without purification.

Step 2: A solution of potassium (E)-(3,4-difluorostyryl)trifluoroborate(100 mg, 0.72 mmol, 1 equiv) and sodium iodide (43 mg, 0.29 mmol, 0.4equiv) in THF (15 mL) was heated to reflux. 2M THF(Trifluoromethyl)trimethylsilane (1.8 mL, 3.6 mmol, 5 equiv) was addeddropwise. After 30 minutes, the reaction mixture was cooled to roomtemperature and filtered. The filtrate was concentrated affording crudepotassium (3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl)trifluoroborate. This material was used without purification. ¹H NMR(400 MHz, DMSO-d₆) δ 7.37-7.24 (m, 1H), 7.23-7.12 (m, 1H), 7.03-6.95 (m,1H), 2.44-2.31 (m, 1H), 0.88-0.70 (m, 1H).

Intermediate 766. racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane

Step 1: To a solution of2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-carboxylic acid (1000mg, 3.84 mmol, 1 equiv) in CH₂Cl₂ (10 mL) was addeddiisopropylmethanediimine (0.66 mL, 4.23 mmol, 1.1 equiv),N,N-dimethylpyridin-4-amine (47 mg, 10 mol %), and2-hydroxyisoindoline-1,3-dione (690 mg, 4.23 mmol, 1.1 equiv). After 18hours, the reaction mixture was filtered over celite with CH₂Cl₂washings and concentrated. The residue was purified by SiO₂chromatography (0-100% EtOAc/Hex), affording 1,3-dioxoisoindolin-2-yl2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-carboxylate (mixtureof cis and trans diastereomers).

Step 2: To a solution of 1,3-dioxoisoindolin-2-yl2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropane-1-carboxylate (781 mg,1.73 mmol, 1 equiv) in EtOAc (10 mL) was added B₂Pin₂ (881 mg, 3.47mmol, 2 equiv) and methyl isonicotinate (0.10 mL, 0.87 mmol, 0.5 equiv).The resulting mixture was heated to 80° C. under an atmosphere of argon.After 16 hours, the reaction mixture was filtered, concentrated, andpurified by SiO₂ chromatography (0-50% EtOAc/Hex), affording racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane.¹H NMR (400 MHz, Chloroform-d) δ 7.08-6.98 (m, 2H), 6.89-6.78 (m, 2H),4.31 (q, J=8.2 Hz, 2H), 2.10-2.05 (m, 1H), 1.25-1.23 (m, 12H), 1.17-1.09(m, 1H), 0.98-0.89 (m, 1H), 0.29-0.15 (m, 1H).

Intermediate 767.2-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: To a solution of2-(4-(2,2-difluoroethoxy)phenyl)cyclopropane-1-carboxylic acid (1000 mg,4.13 mmol, 1 equiv) in CH₂Cl₂ (10 mL) was addeddiisopropylmethanediimine (0.71 mL, 4.54 mmol, 1.1 equiv),N,N-dimethylpyridin-4-amine (50 mg, 10 mol %), and2-hydroxyisoindoline-1,3-dione (741 mg, 4.54 mmol, 1.1 equiv). After 3hours, the reaction mixture was filtered over celite with CH₂Cl₂washings and concentrated. The residue was purified by SiO₂chromatography (0-100% EtOAc/Hex), affording 1,3-dioxoisoindolin-2-yl2-(4-(2,2-difluoroethoxy)phenyl)cyclopropane-1-carboxylate (mixture ofcis and trans diastereomers).

Step 2: To a solution of 1,3-dioxoisoindolin-2-yl2-(4-(2,2-difluoroethoxy)phenyl)cyclopropane-1-carboxylate (1500 mg,3.49 mmol, 1 equiv) in EtOAc (20 mL) was added B2Pin2 (1770 mg, 6.97mmol, 2 equiv) and methyl isonicotinate (0.21 mL, 1.74 mmol, 0.5 equiv).The resulting mixture was heated to 80° C. under an atmosphere of argon.After 16 hours, the reaction mixture was filtered, concentrated, andpurified by SiO₂ chromatography (0-50% EtOAc/Hex), affording racemic2-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (400 MHz, Chloroform-d) δ 7.08-7.00 (m, 2H), 6.86-6.79 (m, 2H),6.08 (tt, J=55.2, 4.1 Hz, 1H), 4.24-4.09 (m, 2H), 2.14-2.04 (m, 1H),1.31-1.23 (m, 12H), 1.18-1.10 (m, 1H), 1.00-0.92 (m, 1H), 0.30-0.19 (m,1H).

Intermediate 768.2-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1: To a solution of racemic(1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropane-1-carboxylic acid (857mg, 3.76 mmol, 1 equiv) in CH₂Cl₂ (12 mL) was addeddiisopropylmethanediimine (0.64 mL, 4.13 mmol, 1.1 equiv),N,N-dimethylpyridin-4-amine (46 mg, 10 mol %), and2-hydroxyisoindoline-1,3-dione (674 mg, 4.13 mmol, 1.1 equiv). After 2hours, the reaction mixture was filtered over celite with CH₂Cl₂washings and concentrated. The residue was purified by SiO₂chromatography (0-100% EtOAc/Hex), affording racemic1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropane-1-carboxylate. ¹H NMR(400 MHz, Chloroform-d) δ 7.92-7.86 (m, 2H), 7.84-7.77 (m, 2H),7.21-7.15 (m, 2H), 7.12-7.05 (m, 2H), 6.50 (t, J=73.8 Hz, 1H), 2.83-2.73(m, 1H), 2.22-2.15 (m, 1H), 1.88-1.78 (m, 1H), 1.62-1.57 (m, 1H).

Step 2: To a solution of racemic1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropane-1-carboxylate(1301 mg, 3.14 mmol, 1 equiv) in EtOAc (15 mL) was added B2Pin2 (1593mg, 6.27 mmol, 2 equiv) and methyl isonicotinate (0.19 mL, 1.57 mmol,0.5 equiv). The resulting mixture was heated to 80° C. under anatmosphere of argon. After 8 hours, the reaction mixture was filtered,concentrated, and purified by SiO₂ chromatography (0-50% EtOAc/Hex),affording racemic2-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.¹H NMR (400 MHz, Chloroform-d) δ 7.09-6.95 (m, 4H), 6.44 (t, J=74.3 Hz,1H), 2.13-2.05 (m, 1H), 1.25 (s, 6H), 1.24 (s, 6H), 1.19-1.13 (m, 1H),1.00-0.93 (m, 1H), 0.29-0.19 (m, 1H).

Intermediate 769.2-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

Step 1: A solution of 4-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol,1 equiv), vinyl trifluoroborate (1842 mg, 13.7 mmol, 1.1 equiv),potassium carbonate (5183 mg, 37.5 mmol, 3 equiv), and(dppf)PdCl₂—CH₂Cl₂ (457 mg, 5 mol %) in 9:1 THF/H₂O (32 mL) was heatedto 85° C. After 20 hours, the reaction mixture was cooled to roomtemperature, diluted with H₂O (25 mL), and extracted with CH₂Cl₂ (3×50mL). The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-50% EtOAc/Hex), affording 2-fluoro-4-vinylbenzonitrile. ¹H NMR (400MHz, Chloroform-d) δ 7.61-7.53 (m, 1H), 7.30-7.19 (m, 2H), 6.70 (dd,J=17.5, 10.9 Hz, 1H), 5.89 (d, J=17.5 Hz, 1H), 5.52 (d, J=10.9 Hz, 1H).

Step 2: To a cooled (0° C.) solution of 2-fluoro-4-vinylbenzonitrile(1670 mg, 11.3 mmol, 1 equiv) and Ru(II)-(R)-Pheox catalyst[Tetrakis(acetonitrile)[2-[(4R)-4,5-dihydro-4-phenyl-2-oxazolyl-N]phenyl]ruthenium(II)Hexafluorophosphate] (72 mg, 1 mol %) in CH₂Cl₂ (113 mL, 0.1M) was addeda 0.2M solution of 1,3-dioxoisoindolin-2-yl 2-diazoacetate (2886 mg,12.5 mmol, 1.1 equiv) in CH₂Cl₂ over 40 minutes. After an additional 5hours at 0° C., the reaction mixture was diluted with MeOH (10 mL) andconcentrated to ˜10 mL. Purification was accomplished by SiO₂chromatography (0-70% EtOAc/Hex), affording 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-cyano-3-fluorophenyl)cyclopropane-1-carboxylate. Theenantiomeric excess was determined to be 95% ee via SFC chiral analysis.¹H NMR (400 MHz, Chloroform-d) δ 7.93-7.88 (m, 2H), 7.84-7.79 (m, 2H),7.59 (dd, J=8.1, 6.6 Hz, 1H), 7.07 (dd, J=8.1, 1.7 Hz, 1H), 7.01 (dd,J=9.8, 1.7 Hz, 1H), 2.84-2.75 (m, 1H), 2.34-2.26 (m, 1H), 1.98-1.89 (m,1H), 1.69-1.61 (m, 1H). ES/MS m/z: 373.00 [M+Na].

Step 3: To a solution of 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(4-cyano-3-fluorophenyl)cyclopropane-1-carboxylate (2830 mg,8.08 mmol, 1 equiv) in EtOAc (50 mL) was added B2Pin2 (4103 mg, 16.2mmol, 2 equiv) and methyl isonicotinate (0.48 mL, 4.04 mmol, 0.5 equiv).The resulting mixture was heated to 80° C. under an atmosphere of argon.After 16 hours, the reaction mixture was filtered, concentrated, andpurified by SiO₂ chromatography (0-20% EtOAc/Hex), affording2-fluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.¹H NMR (400 MHz, Chloroform-d) δ 7.46 (dd, J=8.1, 6.7 Hz, 1H), 6.93 (dd,J=8.1, 1.6 Hz, 1H), 6.86 (dd, J=10.4, 1.6 Hz, 1H), 2.15-2.06 (m, 1H),1.34-1.18 (m, 13H), 1.09-1.00 (m, 1H), 0.42-0.31 (m, 1H).

Intermediate 770.4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane

4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolanewas prepared in the manner described for Intermediate 769 (steps 2-3),but replacing 2-fluoro-4-vinylbenzonitrile with1-(trifluoromethoxy)-4-vinyl-benzene. ¹H NMR (400 MHz, Chloroform-d) δ7.10 (s, 4H), 2.16-2.09 (m, 1H), 1.28 (s, 6H), 1.27 (s, 6H), 1.23-1.16(m, 1H), 1.03-0.96 (m, 1H), 0.34-0.26 (m, 1H). Passed to Hai for Suzukireactions.

Intermediate 771.2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with5-bromo-2-chloro-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ7.38-7.32 (m, 2H), 7.19 (dd, J=8.5, 2.3 Hz, 1H), 2.11-2.05 (m, 1H),1.26-1.23 (m, 13H), 1.03-0.96 (m, 1H), 0.32-0.23 (m, 1H).

Intermediate 772.4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolane

4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolanewas prepared in the manner described for Intermediate 769 (steps 2-3),but replacing 2-fluoro-4-vinylbenzonitrile with1-(trifluoromethyl)-4-vinyl-benzene. ¹H NMR (400 MHz, Chloroform-d) δ7.50 (d, J=8.1 Hz, 2H), 7.18 (d, J=8.1 Hz, 2H), 2.20-2.11 (m, 1H),1.31-1.20 (m, 13H), 1.11-1.02 (m, 1H), 0.41-0.31 (m, 1H).

Intermediate 773.2-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

2-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with1-bromo-4-(difluoromethoxy)benzene. ¹H NMR (400 MHz, Chloroform-d) δ7.09-6.95 (m, 4H), 6.44 (t, J=74.3 Hz, 1H), 2.13-2.05 (m, 1H), 1.25 (s,6H), 1.24 (s, 6H), 1.19-1.13 (m, 1H), 1.00-0.93 (m, 1H), 0.29-0.19 (m,1H).

Intermediate 774.2,6-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2,6-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with4-bromo-2,6-difluoro-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ6.74-6.67 (m, 2H), 2.12-2.06 (m, 1H), 1.35-1.20 (m, 13H), 1.11-1.01 (m,1H), 0.42-0.32 (m, 1H).

Intermediate 775.2,3-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2,3-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with4-bromo-2,3-difluoro-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ7.27-7.19 (m, 1H), 6.74-6.63 (m, 1H), 2.40-2.30 (m, 1H), 1.37-1.19 (m,13H), 1.14-1.08 (m, 1H), 0.44-0.34 (m, 1H).

Intermediate 776.2-methoxy-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-methoxy-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 2-3),but replacing 2-fluoro-4-vinylbenzonitrile with2-methoxy-4-vinyl-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ 7.43(d, J=8.3 Hz, 1H), 6.71-6.64 (m, 2H), 3.92 (s, 3H), 2.18-2.09 (m, 1H),1.32-1.19 (m, 13H), 1.11-1.01 (m, 1H), 0.44-0.35 (m, 1H).

Intermediate 777.2-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with4-bromo-2-methyl-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ 7.47 (d,J=8.1 Hz, 1H), 7.02 (s, 1H), 6.97-6.90 (m, 1H), 2.51 (s, 3H), 2.13-2.07(m, 1H), 1.28-1.25 (m, 13H), 1.10-1.02 (m, 1H), 0.40-0.31 (m, 1H).

Intermediate 778.2-cyclopropyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-cyclopropyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with4-bromo-2-cyclopropyl-benzonitrile.

Intermediate 779.2-fluoro-6-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-fluoro-6-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with4-bromo-2-fluoro-6-methyl-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ6.80 (s, 1H), 6.69-6.59 (m, 1H), 2.48 (s, 3H), 2.11-2.03 (m, 1H),1.30-1.21 (m, 13H), 1.07-0.99 (m, 1H), 0.38-0.28 (m, 1H).

Intermediate 780.2-chloro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2-chloro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with4-bromo-2-chloro-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ 7.51 (d,J=8.0 Hz, 1H), 7.18 (d, J=1.7 Hz, 1H), 7.00 (dd, J=8.0, 1.7 Hz, 1H),2.13-2.05 (m, 1H), 1.33-1.20 (m, 13H), 1.10-1.01 (m, 1H), 0.42-0.30 (m,1H).

Intermediate 781.2,5-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile

2,5-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with4-bromo-2,5-difluoro-benzonitrile. ¹H NMR (400 MHz, Chloroform-d) δ7.25-7.18 (m, 1H), 6.75-6.61 (m, 1H), 2.37-2.27 (m, 1H), 1.37-1.21 (m,13H), 1.13-1.04 (m, 1H), 0.41-0.31 (m, 1H).

Intermediate 782.6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazole

6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazolewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with6-bromo-2-(trifluoromethyl)-1,3-benzothiazole. ¹H NMR (400 MHz,Chloroform-d) δ 8.05 (d, J=8.6 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.30(dd, J=8.6, 1.8 Hz, 1H), 2.32-2.22 (m, 1H), 1.32-1.21 (m, 13H),1.15-1.04 (m, 1H), 0.46-0.33 (m, 1H).

Intermediate 783.4-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole

4-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazolewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with6-bromo-4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 8.05 (s, 1H), 6.95 (s, 1H), 6.55 (d, J=11.0 Hz, 1H),4.88 (q, J=8.4 Hz, 2H), 2.31-2.15 (m, 1H), 1.32-1.20 (m, 13H), 1.12-1.01(m, 1H), 0.44-0.32 (m, 1H). ES/MS m/z: 385.10 [M+H].

Intermediate 784.5-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole

5-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazolewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with6-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ¹H NMR (400 MHz,Chloroform-d) δ 7.97 (s, 1H), 7.31 (d, J=9.6 Hz, 1H), 6.97 (d, J=5.7 Hz,1H), 4.87 (q, J=8.4 Hz, 2H), 2.45-2.34 (m, 1H), 1.33-1.19 (m, 13H),1.11-1.02 (m, 1H), 0.42-0.30 (m, 1H). ES/MS m/z: 385.20 [M+H].

Intermediate 785.7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole

7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazolewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with7-bromo-5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ES/MS m/z: 385.10[M+H].

Intermediate 786.6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazole

6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazolewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with6-bromo-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazole. ¹H NMR(400 MHz, Chloroform-d) δ 7.71 (d, J=8.3 Hz, 1H), 7.18 (s, 1H),7.09-7.02 (m, 1H), 4.94 (q, J=8.3 Hz, 2H), 2.33-2.22 (m, 1H), 1.30-1.21(m, 13H), 1.14-1.04 (m, 1H), 0.46-0.35 (m, 1H).

Intermediate 787.6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-indazole

6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-indazolewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with1-(2,2,2-trifluoro-1-methyl-ethyl)-6-vinyl-indazole. ES/MS m/z: 381.20[M+H].

Intermediate 788.2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine

Step 1: To a solution of 2-chloro-5-vinyl-pyridine (1360 mg, 9.74 mmol,1 equiv) in toluene (20 mL) was added ethyl diazoacetate (1 mL, 9.74mmol, 1 equiv). The reaction mixture was heated to 80° C. After 24hours, the reaction mixture was diluted with MeOH (5 mL) andconcentrated to ˜5 mL. Purification was accomplished by SiO₂chromatography (0-100% EtOAc/Hex), affording racemic ethyl(1S,2S)-2-(6-chloropyridin-3-yl)cyclopropane-1-carboxylate. ¹H NMR (400MHz, Chloroform-d) δ 8.22 (d, J=2.6 Hz, 1H), 7.35-7.29 (m, 1H), 7.24 (d,J=8.4 Hz, 1H), 4.22-4.15 (m, 2H), 2.54-2.45 (m, 1H), 1.94-1.86 (m, 1H),1.70-1.63 (m, 1H), 1.35-1.25 (m, 4H). ES/MS m/z: 226.10 [M+H].

Step 2: To a solution of racemic ethyl(1S,2S)-2-(6-chloropyridin-3-yl)cyclopropane-1-carboxylate (738 mg, 3.27mmol, 1 equiv) in 5:1 THF:H₂O (5 mL) was added LiOH—H₂O (274 mg, 6.54mmol, 2 equiv). The reaction mixture was heated to 45 C. At t=2 hours,an additional 2 equiv of LiOH—H₂O was added. At t=20 hours, the reactionmixture was neutralized at 0° C. with 2M HCl, then exhaustivelyextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated to afford racemic(1S,2S)-2-(6-chloropyridin-3-yl)cyclopropane-1-carboxylic acid. A smallportion of crude material was purified by SiO₂ chromatography (0-50%MeOH/CH₂Cl₂) for characterization purposes. ¹H NMR (400 MHz,Chloroform-d) δ 8.24 (d, J=2.5 Hz, 1H), 7.39-7.31 (m, 1H), 7.30-7.23 (m,1H), 2.63-2.48 (m, 1H), 1.99-1.87 (m, 1H), 1.79-1.66 (m, 1H), 1.45-1.34(m, 1H). ES/MS m/z: 198.10 [M+H].

Step 3: To a solution of racemic(1S,2S)-2-(6-chloropyridin-3-yl)cyclopropane-1-carboxylic acid (290 mg,1.47 mmol, 1 equiv) in CH₂Cl₂ (10 mL) was addeddiisopropylmethanediimine (0.27 mL, 1.76 mmol, 1.2 equiv), DMAP (36 mg,10 mol %), and 2-hydroxyisoindoline-1,3-dione (287 mg, 1.76 mmol, 1.2equiv). After 5 hours, the reaction mixture was filtered with CH₂Cl₂washings and concentrated. The residue was purified by SiO₂chromatography (0-20% MeOH/CH₂Cl₂), affording racemic1,3-dioxoisoindolin-2-yl(1S,2S)-2-(6-chloropyridin-3-yl)cyclopropane-1-carboxylate. ¹H NMR (400MHz, Chloroform-d) δ 8.29 (d, J=2.5 Hz, 1H), 7.98-7.87 (m, 2H),7.85-7.77 (m, 2H), 7.47-7.39 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 2.81-2.72(m, 1H), 2.30-2.19 (m, 1H), 1.94-1.86 (m, 1H), 1.67-1.59 (m, 1H). ES/MSm/z: 343.00 [M+H].

Step 4: To a solution of racemic 1,3-dioxoisoindolin-2-yl(1S,2S)-2-(6-chloropyridin-3-yl)cyclopropane-1-carboxylate (525 mg, 1.53mmol, 1 equiv) in EtOAc (8 mL) was added B2Pin2 (778 mg, 3.06 mmol, 2equiv) and methyl isonicotinate (0.091 mL, 0.77 mmol, 0.5 equiv). Theresulting mixture was heated to 80° C. under an atmosphere of argon.After 12 hours, the reaction mixture was filtered, concentrated, andpurified by SiO₂ chromatography (0-20% EtOAc/Hex), affording racemic2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine.¹H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J=2.5 Hz, 1H), 7.31-7.24 (m,1H), 7.24-7.18 (m, 1H), 2.11-2.05 (m, 1H), 1.31-1.18 (m, 13H), 1.04-0.97(m, 1H), 0.33-0.23 (m, 1H). ES/MS m/z: 280.00 [M+H].

Intermediate 789.6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazole

6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with6-vinyl-1,3-benzothiazole. ¹H NMR (400 MHz, Chloroform-d) δ 8.90 (s,1H), 8.00 (d, J=8.5 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.23 (dd, J=8.5,1.8 Hz, 1H), 2.30-2.22 (m, 1H), 1.29-1.20 (m, 13H), 1.14-1.03 (m, 1H),0.43-0.31 (m, 1H). ES/MS m/z: 302.20 [M+H].

Intermediate 790.2-methyl-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazole

2-methyl-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with2-methyl-6-vinyl-1,3-benzothiazole. ¹H NMR (400 MHz, Chloroform-d) δ7.81 (d, J=8.4 Hz, 1H), 7.57-7.51 (m, 1H), 7.16 (dd, J=8.4, 1.9 Hz, 1H),2.82 (s, 3H), 2.29-2.15 (m, 1H), 1.30-1.16 (m, 13H), 1.13-0.98 (m, 1H),0.42-0.27 (m, 1H). ES/MS m/z: 316.20 [M+H].

Intermediate 791.5-chloro-3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine

5-chloro-3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridinewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with5-chloro-3-fluoro-2-vinyl-pyridine. ¹H NMR (400 MHz, Chloroform-d) δ8.20 (d, J=2.0 Hz, 1H), 7.32 (dd, J=9.2, 2.0 Hz, 1H), 2.53-2.41 (m, 1H),1.47-1.36 (m, 1H), 1.31-1.16 (m, 13H), 0.75-0.64 (m, 1H). ES/MS m/z:298.10 [M+H].

Intermediate 792 and 793.5-chloro-3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridineand5-chloro-3-fluoro-2-((1R,2R)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine

5-chloro-3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridineand5-chloro-3-fluoro-2-((1R,2R)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridinewere obtained via SFC chiral separation of racemic ethyl(1S,2S)-2-(5-chloro-3-fluoro-2-pyridyl)cyclopropanecarboxylate (in themanner described for step 1 of Intermediate 788) and subsequentprocessing in the manner described for steps 2-4 of Intermediate 788.

Intermediate 794.5-chloro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine

5-chloro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridinewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with5-chloro-2-vinyl-pyridine. ¹H NMR (400 MHz, Chloroform-d) δ 8.38 (d,J=2.5 Hz, 1H), 7.52 (dd, J=8.4, 2.5 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H),2.27-2.17 (m, 1H), 1.36-1.15 (m, 14H), 0.66-0.55 (m, 1H). ES/MS m/z:280.10 [M+H].

Intermediate 795.3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-5-(trifluoromethyl)pyridine

3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-5-(trifluoromethyl)pyridinewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with3-fluoro-5-(trifluoromethyl)-2-vinyl-pyridine. ¹H NMR (400 MHz,Chloroform-d) δ 8.49 (bs, 1H), 7.48 (dd, J=9.3, 1.9 Hz, 1H), 2.60-2.51(m, 1H), 1.53-1.43 (m, 1H), 1.33-1.18 (m, 13H), 0.84-0.75 (m, 1H). ES/MSm/z: 332.10 [M+H].

Intermediate 796.6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with1-(2,2,2-trifluoroethyl)-6-vinyl-pyrazolo[4,3-c]pyridine. ES/MS m/z:368.20 [M+H].

Intermediate 797.7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with7-fluoro-1-(2,2,2-trifluoroethyl)-6-vinyl-pyrazolo[4,3-c]pyridine. ES/MSm/z: 386.20 [M+H].

Intermediate 798.6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with1-(2,2,2-trifluoroethyl)-6-vinyl-pyrazolo[3,4-b]pyridine. ES/MS m/z:368.20 [M+H].

Intermediate 799.6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 788, but replacing 2-chloro-5-vinyl-pyridine with1-(2,2,2-trifluoroethyl)-6-vinyl-pyrazolo[4,3-b]pyridine. ES/MS m/z:368.20 [M+H].

Intermediate 800.6-chloro-8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared

6-chloro-8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(racemic mixture). ES/MS m/z: 304.00 [M+H].

Intermediate 801.2-chloro-5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)benzonitrile

2-chloro-5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 329.05 [M+H].

Intermediate 802.6-chloro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-1,3,2-dioxaborolane.ES/MS m/z: 338.10 [M+H].

Intermediate 803.6-chloro-8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(racemic mixture). ES/MS m/z: 336.00 [M+H].

Intermediate 804.6-chloro-8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.ES/MS m/z: 336.00 [M+H].

Intermediate 805.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrilewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2,6-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 331.10 [M+H].

Intermediate 806.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrilewas prepared in the manner described for Intermediate 5, but replacingracemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith2,3-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 331.10 [M+H].

Intermediate 807.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-methoxy-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 325.20 [M+H].

Intermediate 808.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 309.10 [M+H].

Intermediate 809.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-cyclopropylbenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-cyclopropylbenzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-cyclopropyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 335.10 [M+H].

Intermediate 810.6-chloro-8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith4,4,5,5-tetramethyl-2-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)-1,3,2-dioxaborolane(racemic mixture). ES/MS m/z: 368.10 [M+H].

Intermediate 811.6-chloro-8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(racemic mixture). ES/MS m/z: 350.10 [M+H].

Intermediate 812.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluoro-6-methylbenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluoro-6-methylbenzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-fluoro-6-methyl-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 327.10 [M+H].

Intermediate 813.2-chloro-4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)benzonitrile

2-chloro-4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-chloro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 329.10 [M+H].

Intermediate 814.4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile

4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2,5-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile.ES/MS m/z: 331.10 [M+H].

Intermediate 815.4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile

4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2,5-difluoro-4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzonitrile,and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 349.10[M+H].

Intermediate 816.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazole

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazolewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazole.ES/MS m/z: 395.10 [M+H].

Intermediate 817.6-chloro-8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-chloro-5-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine(racemic mixture). ES/MS m/z: 305.00 [M+H].

Intermediate 818.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-methyl-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazole.ES/MS m/z: 341.00 [M+H].

Intermediate 819.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith2-methyl-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazole,and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 359.10[M+H].

Intermediate 820.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)benzo[d]thiazole

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)benzo[d]thiazole(racemic mixture), and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 345.10[M+H].

Intermediate 821.6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-chloro-3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine.ES/MS m/z: 323.10 [M+H].

Intermediate 822.6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-chloro-3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine(racemic mixture), and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 341.00[M+H].

Intermediate 823.6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazinewas chirally separated from the racemic Intermediate 822 by SFC AD-Hcolumn (35% MeOH). and

Intermediate 824.6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-chloro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine(racemic mixture). ES/MS m/z: 305.10 [M+H].

Intermediate 825.6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-chloro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)pyridine(racemic mixture), and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine, and was chirallyseparated from the racemic mixture by SFC AD-H column (30% IPA-NH₃).

Intermediate 826.6-chloro-8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith3-fluoro-2-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-5-(trifluoromethyl)pyridine.ES/MS m/z: 357.00 [M+H].

Intermediate 827.6-chloro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith4-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 410.10 [M+H].

Intermediate 828.6-chloro-3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith4-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 428.10[M+H].

Intermediate 829.6-chloro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 410.10 [M+H].

Intermediate 830.6-chloro-3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith5-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 428.10[M+H].

Intermediate 831.6-chloro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole.ES/MS m/z: 410.10 [M+H].

Intermediate 832.6-chloro-3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 428.10[M+H].

Intermediate 833.6-chloro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-chloro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole,and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-[1,2,4]triazolo[1,5-b]pyridazine. ES/MS m/z: 411.10[M+H].

Intermediate 834.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture), and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 411.10[M+H].

Intermediates 835 and 836.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridineand6-((1R,2R)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridineand6-((1R,2R)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewere chirally separated from the racemic Intermediate 834 by SFC AD-Hcolumn (20% EtOH).

Intermediate 837.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith7-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture), and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 429.10[M+H].

Intermediate 838.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine(racemic mixture), and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 411.10[M+H].

Intermediate 839.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridinewas chirally separated from the racemic Intermediate 838 by SFC OJ-Hcolumn (15% EtOH).

Intermediate 840.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(racemic mixture), and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 411.10[M+H].

Intermediates 841 and 842.6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridineand6-((1R,2R)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridineand6-((1R,2R)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewere chirally separated from the racemic Intermediate 840 by SFC AD-Hcolumn (15% IPA-NH₃).

Intermediate 843.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazole.ES/MS m/z: 460.00 [M+H].

Intermediate 844.6-chloro-8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-indazole.ES/MS m/z: 406.20 [M+H].

Intermediate 845.6-chloro-8-((1S,2S)-2-(3,4-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(3,4-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 5, but replacing racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-phenylcyclopropyl)-1,3,2-dioxaborolanewith potassium (3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl)trifluoroborate (racemic mixture). ES/MS m/z: 342.10 [M+H].

Intermediate 846.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(difluoromethyl)benzo[d]thiazole

A solution of racemic ((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)boronic acid(40 mg, 0.17 mmol, 1 equiv), 6-bromo-2-(difluoromethyl)benzo[d]thiazole(53 mg, 0.20 mmol, 1.2 equiv), potassium phosphate tribasic (107 mg,0.51 mmol, 3 equiv), and cataCXium-A-Pd-G3 (12 mg, 10 mol %) in 1:5water:1,4-dioxane (2.5 mL) was degassed with Argon for one minute andheated to 80° C. After 1 hour, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording racemic6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(difluoromethyl)benzo[d]thiazole.ES/MS m/z: 377.00 [M+H].

Intermediate 847.6-chloro-8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with2-bromo-5-(2,2-difluoroethoxy)pyridine. ES/MS m/z: 351.10 [M+H].

Intermediate 848.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine. ES/MS m/z:393.10 [M+H].

Intermediate 849.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine. ES/MS m/z:393.10 [M+H].

Intermediate 850.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine. ES/MS m/z:393.10 [M+H].

Intermediate 851.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazole.ES/MS m/z: 460.00 [M+H].

Intermediate 852.6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas chirally separated from the racemic Intermediate 851 by SFC Cell 2column (15% IPA-NH₃).

Intermediate 853.6-chloro-8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole.ES/MS m/z: 442.10 [M+H].

Intermediate 854.6-chloro-8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with5-bromo-2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole.ES/MS m/z: 442.10 [M+H].

Intermediate 855.6-chloro-8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with2-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)pyridine. ES/MS m/z: 403.10[M+H].

Intermediate 856.6-chloro-8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with2-bromo-5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridine. ES/MSm/z: 411.10 [M+H].

Intermediate 857.7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one

7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-onewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with7-bromo-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one. ES/MS m/z: 419.10[M+H].

Intermediate 858.7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(2,2,2-trifluoroethoxy)quinoline

7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(2,2,2-trifluoroethoxy)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with7-bromo-2-(2,2,2-trifluoroethoxy)quinoline. ES/MS m/z: 419.10 [M+H].

Intermediate 859.6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridine. ES/MS m/z:392.10 [M+H].

Intermediate 860.6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as racemic mixture in the manner described for Intermediate846, but replacing 6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridine.ES/MS m/z: 460.10 [M+H].

Intermediate 861.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-chloro-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine.ES/MS m/z: 461.10 [M+H].

Intermediate 862.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-chloro-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine.ES/MS m/z: 411.10 [M+H].

Intermediate 863.7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with7-bromo-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole.ES/MS m/z: 418.10 [M+H].

Intermediate 864.6-chloro-8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with2-chloro-4-(2-(trifluoromethyl)phenyl)pyridine. ES/MS m/z: 415.10 [M+H].

Intermediate 865.6-chloro-8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with2-chloro-4-(2,4-difluorophenyl)pyridine. ES/MS m/z: 383.10 [M+H].

Intermediate 866.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-chloro-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine.ES/MS m/z: 461.10 [M+H].

Intermediate 867.6-chloro-8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with7-chloro-3-(trifluoromethyl)imidazo[1,5-a]pyridine. ES/MS m/z: 378.10[M+H].

Intermediate 868.7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(2,2,2-trifluoroethoxy)quinoline

7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(2,2,2-trifluoroethoxy)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with7-chloro-5-(2,2,2-trifluoroethoxy)quinoline. ES/MS m/z: 419.10 [M+H].

Intermediate 869.6-chloro-8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazole. ES/MS m/z:428.10 [M+H].

Intermediate 870.6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridine.ES/MS m/z: 460.10 [M+H].

Intermediate 871.8-((1S,3S)-3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,3S)-3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(3,4-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 446.10 [M+H].

Intermediate 872.8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 408.10 [M+H].

Intermediate 873.2-chloro-5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

2-chloro-5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with2-chloro-5-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile.ES/MS m/z: 433.10 [M+H].

Intermediate 874.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 442.10 [M+H].

Intermediate 875.8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 440.20 [M+H].

Intermediate 876.8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 440.20 [M+H].

Intermediate 877.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrile.ES/MS m/z: 435.10 [M+H].

Intermediate 878.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrile.ES/MS m/z: 435.10 [M+H].

Intermediate 879.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrile.ES/MS m/z: 429.20 [M+H].

Intermediate 880.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrile.ES/MS m/z: 413.20 [M+H].

Intermediate 881.2-cyclopropyl-4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

2-cyclopropyl-4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-cyclopropylbenzonitrile.ES/MS m/z: 439.20 [M+H].

Intermediate 882.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 472.20 [M+H].

Intermediate 883.8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 454.20 [M+H].

Intermediate 884.8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 455.20 [M+H].

Intermediate 885.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-1/1)cyclopropyl)-2-fluoro-6-methylbenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluoro-6-methylbenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluoro-6-methylbenzonitrile.ES/MS m/z: 431.20 [M+H].

Intermediate 886.2-chloro-4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

2-chloro-4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with2-chloro-4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile.ES/MS m/z: 433.10 [M+H].

Intermediate 887.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile.ES/MS m/z: 435.10 [M+H].

Intermediate 888.4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrilewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with4-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile.ES/MS m/z: 453.10 [M+H].

Intermediate 889.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazole

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazolewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazole.ES/MS m/z: 499.20 [M+H].

Intermediate 890.8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 409.20 [M+H].

Intermediate 891.2-(difluoromethyl)-6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazole

2-(difluoromethyl)-6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazolewas prepared as racemic mixture in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(difluoromethyl)benzo[d]thiazole(racemic mixture).

Intermediate 892.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole(racemic mixture). ES/MS m/z: 445.20 [M+H].

Intermediate 893.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole(racemic mixture). ES/MS m/z: 463.20 [M+H].

Intermediate 894.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazole

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazolewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazole(racemic mixture). ES/MS m/z: 449.10 [M+H].

Intermediate 895.8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 427.10 [M+H].

Intermediate 896.8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 445.10 [M+H].

Intermediate 897.8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 445.10 [M+H].

Intermediate 898.8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 409.20 [M+H].

Intermediate 899 and 900.8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand8-((1R,2R)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand8-((1R,2R)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewere chirally separated from the racemic mixture by SFC AD-H column (35%EtOH).

Intermediate 901.8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 427.10 [M+H].

Intermediate 902.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 461.10 [M+H].

Intermediate 903.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 497.20 [M+H].

Intermediate 904.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine(racemic mixture). ES/MS m/z: 497.20 [M+H].

Intermediate 905.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(racemic mixture). ES/MS m/z: 497.10 [M+H].

Intermediate 906.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 515.10 [M+H].

Intermediate 907.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine.ES/MS m/z: 515.10 [M+H].

Intermediate 908.6-((1R,2R)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1R,2R)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1R,2R)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine.ES/MS m/z: 515.10 [M+H].

Intermediate 909.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 533.20 [M+H].

Intermediate 910.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine(racemic mixture). ES/MS m/z: 515.10 [M+H].

Intermediate 911.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine.ES/MS m/z: 515.10 [M+H].

Intermediate 912.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(racemic mixture). ES/MS m/z: 515.20 [M+H].

Intermediate 913.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine.ES/MS m/z: 515.20 [M+H].

Intermediate 914.6-((1R,2R)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine

6-((1R,2R)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1R,2R)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine.ES/MS m/z: 515.20 [M+H].

Intermediate 915.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 564.20 [M+H].

Intermediate 916.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 564.20 [M+H].

Intermediate 917.8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 546.10 [M+H].

Intermediate 918.8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 546.10 [M+H].

Intermediate 919.8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 507.10 [M+H].

Intermediate 920.8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 515.10 [M+H].

Intermediate 921.7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one

7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-onewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one(racemic mixture). ES/MS m/z: 523.20 [M+H].

Intermediate 922.7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(2,2,2-trifluoroethoxy)quinoline

7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(2,2,2-trifluoroethoxy)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(2,2,2-trifluoroethoxy)quinoline(racemic mixture). ES/MS m/z: 523.20 [M+H].

Intermediate 923.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 514.20 [M+H].

Intermediate 924.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 532.20 [M+H].

Intermediate 925.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 514.20 [M+H].

Intermediate 926.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 532.20 [M+H].

Intermediate 927.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 514.20 [M+H].

Intermediate 928.6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 532.20 [M+H].

Intermediate 929.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 515.20 [M+H].

Intermediate 930.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 495.40 [M+H].

Intermediate 931.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 564.20 [M+H].

Intermediate 932.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 564.10 [M+H].

Intermediate 933.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 565.20 [M+H].

Intermediate 934.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 515.10 [M+H].

Intermediate 935.7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole(racemic mixture). ES/MS m/z: 522.20 [M+H].

Intermediate 936.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 510.20 [M+H].

Intermediate 937.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 519.20 [M+H].

Intermediate 938.8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 487.10 [M+H].

Intermediate 939.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine(racemic mixture). ES/MS m/z: 565.20 [M+H].

Intermediate 940.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 482.20 [M+H].

Intermediate 941.7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(2,2,2-trifluoroethoxy)quinoline

7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(2,2,2-trifluoroethoxy)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with7-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(2,2,2-trifluoroethoxy)quinoline(racemic mixture). ES/MS m/z: 523.20 [M+H].

Intermediate 942.8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 532.10 [M+H].

Intermediate 943.6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-chloro-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 564.20 [M+H].

Intermediate 944.6-(2,4-dimethoxypyrimidin-5-yl)-8-(6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazine

A solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (120 mg,0.36 mmol, 1 equiv), 6-azaspiro[3.4]octane hydrochloride (60 mg, 0.54mmol, 1.5 equiv), and DIPEA (0.19 mL, 1.07 mmol, 3 equiv) in MeCN (3 mL)was heated to 100° C. After 3 hours, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording6-(2,4-dimethoxypyrimidin-5-yl)-8-(6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 367.20 [M+H].

Intermediate 945.8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with2,2-difluoro-6-azaspiro[3.4]octane hydrochloride. ES/MS m/z: 403.20[M+H].

Intermediate 946.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(methoxymethyl)-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(methoxymethyl)-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with3-(methoxymethyl)-3-methyl-pyrrolidine hydrochloride. ES/MS m/z: 385.20[M+H].

Intermediate 947.3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-6,6-difluoro-3-azabicyclo[3.1.1]heptane

3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-6,6-difluoro-3-azabicyclo[3.1.1]heptanewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with6,6-difluoro-3-azabicyclo[3.1.1]heptane hydrochloride. ES/MS m/z: 389.20[M+H].

Intermediate 948.8-(3-cyclopropylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-cyclopropylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with 3-cyclopropylpyrrolidine. ES/MSm/z: 367.20 [M+H].

Intermediate 949.8-(3-(3,3-difluorocyclobutyl)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-(3,3-difluorocyclobutyl)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with3-(3,3-difluorocyclobutyl)pyrrolidine. ES/MS m/z: 417.20 [M+H].

Intermediate 950.3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1-fluoro-3-azabicyclo[3.1.1]heptane

3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1-fluoro-3-azabicyclo[3.1.1]heptanewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with1-fluoro-3-azabicyclo[3.1.1]heptane hydrochloride. ES/MS m/z: 371.20[M+H].

Intermediate 951.2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2-azaspiro[4.5]decane

2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2-azaspiro[4.5]decanewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with8,8-difluoro-2-azaspiro[4.5]decane hydrochloride. ES/MS m/z: 431.20[M+H].

Intermediate 952.8-(3-((1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

8-(3-((1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with1-(pyrrolidin-3-ylmethyl)triazole. ES/MS m/z: 408.20 [M+H].

Intermediate 953.6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(prop-2-yn-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(prop-2-yn-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with 3-prop-2-ynylpyrrolidine. ES/MSm/z: 365.20 [M+H].

Intermediate 954. tert-butyl6-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate

tert-butyl6-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1,6-diazaspiro[3.4]octane-1-carboxylatewas prepared in the manner described for Intermediate 944, but replacing6-azaspiro[3.4]octane hydrochloride with tert-butyl1,7-diazaspiro[3.4]octane-1-carboxylate. ES/MS m/z: 468.20 [M+H].

Intermediate 955. 6-chloro-N-isobutylimidazo[1,2-b]pyridazin-8-amine

6-chloro-N-isobutylimidazo[1,2-b]pyridazin-8-amine was prepared asfollows: A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (168 mg, 0.72 mmol, 1 equiv),isobutylamine (0.11 mL, 1.1 mmol, 1.5 equiv), DIPEA (0.19 mL, 1.1 mmol,1.1 equiv), and MeCN (4 mL). The reaction mixture was heated to 80° C.,until done, 1 hour. The mixture was cooled diluted with EtOAc and waterand the layers separated. The organic layer was dried over sodiumsulfate, concentrated and purified by flash column chromatography togive 6-chloro-N-isobutylimidazo[1,2-b]pyridazin-8-amine. ES/MS m/z:225.24.

Intermediate 956.6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-isobutylimidazo[1,2-b]pyridazin-8-amine

6-chloro-N-isobutylimidazo[1,2-b]pyridazin-8-amine (152 mg, 0.68 mmol)and (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (272 mg, 1.0 mmol)were dissolved in dioxane/water (3/1, 5 mL). To the reaction mixture wasadded sodium carbonate (215 mg, 2.0 mmol) and Pd(dppf)Cl₂ (41 mg, 0.1mmol). The reaction mixture was then purged with argon for 10 mins andthen heated at 100° C. for 30 minutes. The reaction mixture was cooled,diluted with EtOAc and water, the organic layer was dried over sodiumsulfate, concentrated, and purified by flash column chromatography toafford6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-isobutylimidazo[1,2-b]pyridazin-8-amine.ES/MS m/z: 413.03 [M+H].

Intermediate 957.6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine

6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine was preparedas follows: A microwave vial was charged with8-bromo-6-chloroimidazo[1,2-b]pyridazine (200 mg, 0.86 mmol, 1 equiv),(4-methoxyphenyl)methanamine (0.11 mL, 1.3 mmol, 1.5 equiv), DIPEA (0.22mL, 1.3 mmol, 1.5 equiv), and MeCN (4 mL). The reaction mixture washeated to ° C., until done, 1 hour. The mixture was cooled diluted withEtOAc and water and the layers separated. The organic layer was driedover sodium sulfate, concentrated and purified by flash columnchromatography to give6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine. ES/MS m/z:289.11.

Intermediate 958.6-chloro-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine

6-chloro-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-aminewas prepared as follows: A microwave vial was charged with6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine (80 mg, 0.28mmol, 1 equiv), DMF (2 mL) followed by sodium hydride 60% dispersion inmineral oil (13 mg, 0.33 mmol, 1.2 equiv). After the mixture was stirredfor 10 minutes then 2,2-difluoroethyl trifluoromethanesulfonate (119 mg,mmol, 2 equiv) was added the mixture was heated was heated to 60° C.,until done, 1 hour. The mixture was cooled diluted with EtOAc and waterand the layers separated. The organic layer was dried over sodiumsulfate, concentrated and purified by flash column chromatography togive6-chloro-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine.ES/MS m/z: 353.02.

Intermediate 959.6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine

6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine (82 mg, 0.23mmol) and (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (93 mg, 1.5mmol) were dissolved in dioxane/water (3/1, 2 mL). To the reactionmixture was added sodium carbonate (74 mg, 3.0 mmol) and Pd(dppf)Cl₂ (14mg, 0.1 mmol). The reaction mixture was then purged with argon for minsand then heated at 100° C. for 30 minutes. The reaction mixture wascooled, diluted with EtOAc and water, the organic layer was dried oversodium sulfate, concentrated, and purified by flash columnchromatography to afford6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine.ES/MS m/z: 541.77 [M+H].

Intermediate 960.6-chloro-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazine

6-chloro-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazinewas prepared as follows: To a vial add3,3,3-trifluoro-2,2-dimethyl-propan-1-ol (153 mg, 1.1 mmol) and Me-THF(2 ml) then carefully add sodium hydride 60% dispersion in mineral oil(16.5 mg, mmol) allowing to stir for 10 minutes then add8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.22 mmol) then cap andheat to 70° C. for 2 hr. The reaction was cooled quenched with water,extracted 2×EtOAc, the organic layer was dried over sodium sulfate,concentrated, and used crude in the next reaction. ES/MS m/z: 294.21[M+H].

Intermediate 961.6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazine

6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 959, but replacing6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine with6-chloro-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 482.53 [M+H].

Intermediate 962. 6-chloro-8-fluoroimidazo[1,2-b]pyridazine

8-bromo-6-chloroimidazo[1,2-b]pyridazine (3 g, 13 mmol), potassiumfluoride (4.4 g, mmol), 18-crown-6 (3.4 g, 13 mmol) and DMF (15 ml) thereaction was stirred for 7 hours at 100° C. The reaction is then cooledto RT, diluted with DCM and filtered to remove solids. The cake isrinsed with DCM, the resulting mixture is purified by flash columnchromatography to 6-chloro-8-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z:172.09 [M+H].

Intermediate 963.6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine

6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazinewas prepared in the manner described for Intermediate 959, but replacing6-chloro-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine with to6-chloro-8-fluoroimidazo[1,2-b]pyridazine. ES/MS m/z: 359.84 [M+H].

Intermediate 964. 3-ethynyl-3-methyl-pyrrolidine

3-ethynyl-3-methyl-pyrrolidine was prepared as follows: To a solution oftert-butyl 3-ethynyl-3-methyl-pyrrolidine-1-carboxylate (50 mg, 0.24mmol, 1 equiv) in DCM (1 mL) was added TFA solution (0.5 mL). Thereaction vessel was stirred until complete (0.5 hr), the mixture is thenconcentrated and used as is in next reaction. ES/MS: 110.22 [M+1].

Intermediate 965.6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine

6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared as follows: A microwave vial was charged with3-ethynyl-3-methyl-pyrrolidine (13 mg, 0.12 mmol), DIPEA (0.1 mL, 0.56mmol), and MeCN (2 mL) then6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine(44 mg, 0.12 mmol). The reaction mixture was heated to 80° C., untildone, 2 hour. The mixture was cooled diluted with EtOAc and water andthe layers separated. The organic layer was dried over sodium sulfate,concentrated and purified by flash column chromatography to give6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 449.06 [M+1].

Intermediate 966.6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-bromoimidazo[1,2-b]pyridazine

6,8-dibromoimidazo[1,2-b]pyridazine (100 mg, 0.36 mmol),(2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (85 mg, 0.32 mmol) weredissolved in dioxane (1.5 ml) and 1 N NaOH (0.5 ml). To the reactionmixture was added tri-(2-furyl)phosphine (17 mg, 0.07 mmol) and Pd(dba)₂(21 mg, 0.11 mmol). The reaction mixture was then purged with argon for10 mins and then heated at 80° C. for 60 minutes. The reaction mixturewas cooled, diluted with EtOAc and water, the organic layer was driedover sodium sulfate, concentrated, and purified by flash columnchromatography to afford6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-bromoimidazo[1,2-b]pyridazine.ES/MS m/z: 419.86 and 421.88 [M+H].

Intermediate 967.4-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-methylbut-3-yn-2-ol

8-bromo-6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (15mg, 0.04 mmol), 2-Methyl-3-butyn-2-ol (0.007 ml, 0.07 mmol) weredissolved in Me-THF (2 ml). To the reaction mixture was addeddiethylamine (0.04 ml, 0.36 mmol), copper iodide (0.68 mg, 0.004 mmol)and Pd(Cl)₂(Ph₃)₂ (2.5 mg, 0.004 mmol). The reaction mixture was thenpurged with argon for 10 mins and then heated at 80° C. for 30 minutes.The reaction mixture was cooled, diluted with EtOAc and water, theorganic layer was dried over sodium sulfate, concentrated, and purifiedby flash column chromatography to afford4-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-methylbut-3-yn-2-ol.ES/MS m/z: 424.80 [M+H].

Intermediate 968 and 969.3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-oland8,8′-((2,2-difluoropropane-1,3-diyl)bis(oxy))bis(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine)

3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-oland8,8′-((2,2-difluoropropane-1,3-diyl)bis(oxy))bis(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine)were prepared as follows: To a vial add 2,2-difluoropropane-1,3-diol(468 mg, 4.2 mmol) and THF (10 ml) then carefully add sodium hydride 60%dispersion in mineral oil (64 mg, 1.7 mmol) allowing to stir for 10minutes then add6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine(300 mg, 0.83 mmol) the reaction was complete after 10 minutes. Thereaction was quenched with water, extracted 2×EtOAc, the organic layerwas dried over sodium sulfate, concentrated, and purified by flashcolumn chromatography to give the two title compounds. ES/MS m/z:product 1: 452.07 and product 2: 791.23 [M+H].

Intermediate 970.6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazine

6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewas prepared as follows: To a vial add 2,2-difluorobutan-1-ol (23 mg,0.21 mmol) and THF (2 ml) then carefully add sodium hydride 60%dispersion in mineral oil (3.2 mg, 0.08 mmol) allowing to stir for 10minutes then add6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine(15 mg, 0.04 mmol) the reaction was complete after 10 minutes. Thereaction was quenched with water, extracted 2×EtOAc, the organic layerwas dried over sodium sulfate, concentrated, and used crude in the nextreaction. ES/MS m/z: 450.22 [M+H].

Intermediate 971.3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate

3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate was prepared as follows: To a vial add3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol(15 mg, 0.03 mmol) and DCM (2 ml) then add DiPEA (0.18 ml, 0.10 mmol)and 2-isocyanatopropane (0.03 ml, 0.33 mmol) the mixture was then heatedat 60° C. overnight. The reaction was quenched with water, extracted2×EtOAc, the organic layer was dried over sodium sulfate, concentrated,and purified by flash column chromatography to give the title compound.ES/MS m/z: 537.23 [M+H].

Intermediate 972.6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluoro-3-(pyridin-2-yloxy)propoxy)imidazo[1,2-b]pyridazine

6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluoro-3-(pyridin-2-yloxy)propoxy)imidazo[1,2-b]pyridazinewas prepared as follows: To a vial add3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol(15 mg, mmol) and THF (2 ml) then carefully add sodium hydride 60%dispersion in mineral oil (2.5 mg, 0.07 mmol) allowing to stir for 10minutes then add 2-fluoropyridine (16 mg, 0.17 mmol) the reaction washeated at 60° C. for 1.5 hours. The reaction was quenched with water,extracted 2×EtOAc, the organic layer was dried over sodium sulfate,concentrated, and, and purified by flash column chromatography to givethe title compound. ES/MS m/z: 529.10 [M+H].

Intermediate 973.3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,2,2-trifluoroethyl) carbonate

3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,2,2-trifluoroethyl) carbonate was prepared as follows: To a vial add3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol(15 mg, 0.03 mmol) and DCM (2 ml) then add DiPEA (0.06 ml, 0.33 mmol)and 2,2,2-trifluoroethyl carbonochloridate (54 mg, 0.33 mmol) themixture was then heated at 60° C. overnight. The reaction was quenchedwith water, extracted 2×EtOAc, the organic layer was dried over sodiumsulfate, concentrated, and purified by flash column chromatography togive the title compound. ES/MS m/z: 578.09 [M+H].

Intermediate 974. Tert-butyl(S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidine-1-carboxylate

Tert-butyl(S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidine-1-carboxylatewas prepared as follows: A microwave vial was charged with copper(I)iodide (32 mg, 0.168 mmol, 0.25 equiv),3,4,7,8-tetramethyl-1,10-phenanthroline (32 mg, 0.134 mmol, 0.2 equiv),cesium carbonate (328 mg, 1.01 mmol, 1.5 equiv), tert-butyl(S)-3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (150 mg, 0.672 mmol,1 equiv) and 6-bromo-1-(2,2,2-trifluoroethyl)-1H-indazole (188 mg, 0.672mmol, 1 equiv). The vial was sealed and toluene (2.0 mL) was added underan Argon atmosphere. The reaction mixture was gradually heated to 120°C. and stirred overnight. After cooling to room temperature, the mixturewas diluted with EtOAc and filtered through a pad of Celite. Thefiltrate was concentrated under reduced pressure and the crude materialwas purified by silica gel chromatography (0-100% EtOAc in hexanes) toafford the title compound. ES/MS m/z: 422.1 [M+H]. ¹H NMR (400 MHz,Chloroform-d) δ 8.01 (s, 1H), 7.67 (d, J=8.7 Hz, 1H), 6.91 (dd, J=8.8,2.1 Hz, 1H), 6.87 (s, 1H), 4.95-4.79 (m, 3H), 3.95-3.60 (m, 4H),1.51-1.46 (m, 9H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −71.17,−105.56-−107.02 (m), −120.14-−121.91 (m).

Intermediate 975.(S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazolehydrochloride

(S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazolehydrochloride was prepared as follows: A solution of tert-butyl(S)-3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidine-1-carboxylate(100 mg, 0.237 mmol, 1 equiv) in 4 M HCl in dioxane (2.0 mL, 34 equiv)was stirred at room temperature for 2 h and 30 min prior toconcentration in vacuo to afford the title compound in quantitativeyield. ES/MS m/z: 322.0 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 10.33 (s,3H), 8.16-8.12 (m, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.55-7.51 (m, 1H),6.98-6.92 (m, 1H), 5.44-5.30 (m, 3H), 3.95-3.29 (m, 4H).

The title compound was purified by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini-NX column) to afford it as the TFA salt, which was used in thesubsequent reaction.

Intermediate 976.(S)-6-chloro-8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine

(S)-6-chloro-8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazinewas prepared as follows: A solution of8-bromo-6-chloroimidazo[1,2-b]pyridazine (10 mg, 0.041 mmol, 1 equiv)and(S)-6-((4,4-difluoropyrrolidin-3-yl)oxy)-1-(2,2,2-trifluoroethyl)-1H-indazoletrifluoroacetate (18 mg, 0.041 mmol, 1 equiv) in ACN (2.0 mL) was addedDIPEA (0.02 mL, 0.099 mmol, 2.4 equiv). The solution was heated to 85°C. and stirred overnight. The temperature was increased to 100° C. andthe reaction mixture was stirred for an additional 6 h. Additional DIPEA(0.20 mL, 1.15 mmol) was added and the solution was stirred at 120° C.overnight. The reaction mixture was diluted with water and the resultingsolids filtered. The solids were dissolved in EtOAc and the filtrateconcentrated to afford the title compound. ES/MS m/z: 473.0 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 8.15-8.08 (m, 2H), 7.74 (d, J=8.7 Hz, 1H),7.61-7.54 (m, 2H), 6.98 (dd, J=8.8, 2.0 Hz, 1H), 6.23 (s, 1H), 5.52-5.30(m, 3H), 4.75-3.86 (m, 4H).

Intermediate 977.(S)-8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-0)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

(5)-8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewas prepared as follows: A microwave vial was charged with(S)-6-chloro-8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine(10 mg, 0.022 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(5 mg, 0.030 mmol, 1.35 equiv), Pd(dppf)Cl₂CH₂Cl₂ (2 mg, 0.002 mmol, 0.1equiv) and cesium carbonate (14 mg, 0.044 mmol, 2 equiv). To this wasadded 1,4 dioxane (3.0 mL) and water (0.50 mL). The reaction mixture washeated at 80° C. and stirred overnight. Additional(2,4-dimethoxypyrimidin-5-yl)boronic acid (14 mg, 0.076 mmol) andPd(dppf)Cl₂CH₂Cl₂ (20 mg, 0.024 mmol) was added and the solution wasstirred at ° C. for an additional 5 h and 40 min. After cooling to roomtemperature, the mixture was diluted with EtOAc and filtered through apad of Celite. The filtrate was concentrated under reduced pressure andthe crude material was purified by silica gel chromatography (0-100%EtOAc in hexanes) to afford the title compound. ES/MS m/z: 577.1 [M+H].

Intermediate 978.6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one

To a solution of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one(0.5 g, 2.07 mmol, 1 equiv) in DMF (4 mL) was added potassium carbonate(860 mg, 6.22 mmol, 3 equiv) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (722 mg, 3.11 mmol, 1.5 equiv). The reactionmixture was heated to 80 C. After 2 hours, the reaction mixture wasdiluted with brine (50 mL) and extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-100% EtOAc/Hex),affording6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one.ES/MS m/z: 323.10 [M+H]

Intermediate 979.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridinewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine. ES/MSm/z: 411.10 [M+H].

Intermediate 980.6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one

6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-onewas prepared as a racemic mixture in the manner described forIntermediate 352, but replacing 2-bromo-5-(difluoromethoxy)pyridine with6-bromo-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one.ES/MS m/z: 436.40 [M+H].

Intermediate 981.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine(racemic mixture). ES/MS m/z: 515.10 [M+H].

Intermediate 982.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridinewas chirally separated from the racemic Intermediate 981 by SFC AD-Hcolumn (20% EtOH). ES/MS m/z: 514.20 [M+H].

Intermediate 983.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one(Racemic Mixture)

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one(racemic mixture) was prepared in the manner described for Intermediate18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-[(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one(racemic mixture). ES/MS m/z: 540.20 [M+H].

Intermediate 984.6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-one

6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-2-onewas chirally separated from the racemic Intermediate 983 by SFC Cell 2column (20% EtOH). ES/MS m/z: 540.20 [M+H].

Intermediate 985. 6-bromo-8-(2,2,2-trifluoroethoxy)quinoline

To a solution of 6-bromoquinolin-8-ol (300 mg, 1.34 mmol, 1 equiv) inDMF (4 mL) was added potassium carbonate (555 mg, 4.02 mmol, 3 equiv)and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.290 mL, 2.01 mmol,1.5 equiv). The reaction mixture was heated to 80° C. After 2 hours, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording 6-bromo-8-(2,2,2-trifluoroethoxy)quinoline. ¹H NMR(400 MHz, DMSO-d₆) δ 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.34 (dd, J=8.4, 1.7Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.63 (dd, J=8.4, 4.2 Hz, 1H), 7.52 (d,J=2.0 Hz, 1H), 5.03 (q, J=8.8 Hz, 2H). ES/MS m/z: 306.00 [M+H].

Intermediate 986.6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-8-(2,2,2-trifluoroethoxy)quinoline

6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-8-(2,2,2-trifluoroethoxy)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6-bromo-8-(2,2,2-trifluoroethoxy)quinoline. ES/MS m/z: 419.10 [M+H].

Intermediate 987.6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-8-(2,2,2-trifluoroethoxy)quinoline

6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-8-(2,2,2-trifluoroethoxy)quinolinewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-8-(2,2,2-trifluoroethoxy)quinoline.ES/MS m/z: 523.20 [M+H].

Intermediate 988.6′-bromo-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

To a solution of 6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one (200mg, 0.84 mmol, 1 equiv) in DMF (3 mL) was added potassium carbonate (348mg, 2.52 mmol, 3 equiv) and 2,2-difluoropropyl trifluoromethanesulfonate(287 mg, 1.26 mmol, 1.5 equiv). The reaction mixture was heated to 80°C. After 2 hours, the reaction mixture was directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording6′-bromo-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.¹H NMR (400 MHz, DMSO-d6) δ 7.40 (d, J=1.7 Hz, 1H), 7.21 (dd, J=8.0, 1.7Hz, 1H), 7.01 (d, J=8.0 Hz, 1H), 4.27 (t, J=14.8 Hz, 2H), 1.78-1.51 (m,7H).

Intermediate 989.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6′-bromo-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 429.10 [M+H].

Intermediate 990.1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 533.20 [M+H].

Intermediate 991.6′-bromo-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one

To a solution of 6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one (190mg, 0.80 mmol, 1 equiv) in DMF (3 mL) was added potassium carbonate (331mg, 2.39 mmol, 3 equiv) and 1-(bromomethyl)-1-fluorocyclopropane (122mg, 0.80 mmol, 1 equiv). The reaction mixture was heated to 80° C. After20 hours, the reaction mixture was directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording6′-bromo-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one.¹H NMR (400 MHz, DMSO-d6) δ 7.40 (t, J=1.5 Hz, 1H), 7.19 (dd, J=7.9, 1.8Hz, 1H), 7.00 (d, J=7.9 Hz, 1H), 4.19 (d, J=21.8 Hz, 2H), 1.71-1.65 (m,2H), 1.60-1.54 (m, 2H), 1.10-0.98 (m, 2H), 0.93-0.84 (m, 2H). 19F NMR(376 MHz, DMSO-d6) δ −181.67-−182.22 (m).

Intermediate 992.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6′-bromo-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 423.10 [M+H].

Intermediate 993.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 527.30 [M+H].

Intermediate 994.6′-bromo-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

To a solution of 6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one (190mg, 0.80 mmol, 1 equiv) in DMF (3 mL) was added potassium carbonate (331mg, 2.39 mmol, 3 equiv) and 2,2,3,3-tetrafluoropropyltrifluoromethanesulfonate (211 mg, 0.80 mmol, 1 equiv). The reactionmixture was heated to 80° C. After 1 hour, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording6′-bromo-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 352.00 [M+H].

Intermediate 995.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6′-bromo-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 465.20 [M+H].

Intermediate 996.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 569.20 [M+H].

Intermediate 997.6′-bromo-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

To a solution of 6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one (150mg, 0.63 mmol, 1 equiv) in DMF (3 mL) was added potassium carbonate (261mg, 1.89 mmol, 3 equiv) and 2,2,3,3,3-pentafluoropropyltrifluoromethanesulfonate (178 mg, 0.63 mmol, 1 equiv). The reactionmixture was heated to 80° C. After 2 hours, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording6′-bromo-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 370.00 [M+H].

Intermediate 998.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6′-bromo-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 483.10 [M+H].

Intermediate 999.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 587.20 [M+H].

Intermediate 1000.6′-bromo-1′-(2-cyclopropyl-2,2-difluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

To a solution of 6′-bromospiro[cyclopropane-1,3′-indolin]-2′-one (100mg, 0.42 mmol, 1 equiv) in DMF (3 mL) was added potassium carbonate (261mg, 1.89 mmol, 3 equiv) and 2-cyclopropyl-2,2-difluoroethyltrifluoromethanesulfonate (107 mg, 0.42 mmol, 1 equiv). The reactionmixture was heated to 80° C. After 2 hours, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording6′-bromo-1′-(2-cyclopropyl-2,2-difluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.¹H NMR (400 MHz, DMSO-d6) δ 7.39 (s, 1H), 7.20 (dd, J=8.0, 1.7 Hz, 1H),7.00 (d, J=8.0 Hz, 1H), 4.35 (t, J=14.5 Hz, 2H), 1.72-1.65 (m, 2H),1.61-1.53 (m, 2H), 1.54-1.38 (m, 1H), 0.64-0.49 (m, 4H).

Intermediate 1001.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2-cyclopropyl-2,2-difluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2-cyclopropyl-2,2-difluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 846, but replacing6-bromo-2-(difluoromethyl)benzo[d]thiazole with6′-bromo-1′-(2-cyclopropyl-2,2-difluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 455.20 [M+H].

Intermediate 1002.1′-(2-cyclopropyl-2,2-difluoroethyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(Racemic Mixture)

1′-(2-cyclopropyl-2,2-difluoroethyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared as a racemic mixture in the manner described forIntermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with1′-(2-cyclopropyl-2,2-difluoroethyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 559.20 [M+H].

Intermediate 1003.1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 769 (steps 1-3),but replacing 4-bromo-2-fluorobenzonitrile with6′-bromo-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 404.20 [M+H].

Intermediate 1004.6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 238, but replacing4-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrilewith1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one,and 8-bromo-6-chloro-imidazo[1,2-b]pyridazine with8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine. ES/MS m/z: 447.10[M+H].

Intermediate 1005.1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 18, but replacing6-chloro-8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazine with6′-((1S,2S)-2-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2-difluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 551.20 [M+H].

Intermediate 1006.(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile

(3S)-1-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(58 mg, 0.15 mmol) was dissolved in NMP (2 mL), to the reaction mixturewas added 4-fluoro-2-(trifluoromethoxy)benzonitrile (60 mg, 0.29 mmol)and cesium carbonate (143 mg, 0.44 mmol). The reaction mixture washeated at 85° C. overnight. The reaction mixture was then diluted withEtOAc, washed with brine, evaporated organic solvent and purified theresidue with combi-flash column to afford(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 582.10.

Intermediate 1007.(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile

(3S)-1-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(55 mg, 0.145 mmol) was dissolved in NMP (2 mL), to the reaction mixturewas added 4-fluoro-2-(trifluoromethoxy)benzonitrile (60 mg, 0.29 mmol)and cesium carbonate (142 mg, 0.44 mmol). The reaction mixture washeated at 85° C. overnight. The reaction mixture was then diluted withEtOAc, washed with brine, evaporated organic solvent and purified theresidue with combi-flash column to afford(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 564.10.

Intermediate 1008.(S)-8-(4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine

(3S)-1-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(103 mg, 0.26 mmol) was dissolved in DMF (4 mL), to the reaction mixturewas added NaH (60% dispersion in mineral oil, 30 mg, 0.78 mmol) andstirred for 10 min at RT. Then 4-(difluoromethyl)-2,5-difluoro-pyridine(86 mg, 0.52 mmol) was added and the reaction mixture was heated at 85°C. for 30 mins. The reaction mixture was then diluted with EtOAc, washedwith brine, evaporated organic solvent and purified the residue withcombi-flash column to afford(S)-8-(4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 542.10.

Intermediate 1009.(S)-8-(4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

(3S)-1-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(107 mg, 0.28 mmol) was dissolved in toluene (2 mL), cesium carbonate(138 mg, mmol), copper iodide (13.5 mg, 0.07 mmol) and3,4,7,8-Tetramethyl-1,10-phenanthroline (13.4 mg, 0.057 mmol) were addedto the reaction mixture and the reaction mixture was heated at 110° C.for 30 mins. The reaction mixture was then diluted with EtOAc, washedwith brine, evaporated organic solvent and purified the residue withcombi-flash column to afford(S)-8-(4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-[1,2-b]pyridazine.ES/MS m/z: 523.20.

Intermediate 1010.6′-bromo-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

To a solution of 6′-bromospiro[cyclopropane-1,3′-indoline]-2′-one (600mg, 2.52 mmol) in DMF was added NaH (97 mg, 2.52 mmol) and3,3,3-trifluoropropyl trifluoromethanesulfonate (930 mg, 3.78 mmol). Thereaction mixture was heated to 110° C. for 3 h. The reaction mixture wascooled to RT, diluted with brine (50 mL), and extracted with 80%EtOAc/Hex (2×100 mL). The combined organic layers were concentrated andpurified by Combi-Flash column chromatography to afford6′-bromo-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 344.00.

Intermediate 1011.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared as a racemic mixture in the manner described forIntermediate 498, but replacing 5-bromo-2-methylbenzo[d]thiazole with6′-bromo-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 447.10.

Intermediate 1012.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared in the manner described for Intermediate 523,but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 551.20.

Intermediate 1013.6′-bromo-7′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one

6-bromo-4-fluoro-indolin-2-one (1.5 g, 6.52 mmol) was dissolved in THF(5 mL), to the mixture was added LDA (1M in THF/hexane) at −78 degreefollowed by addition of 1,2-dibromoethane (0.72 g, 3.83 mmol). Thereaction mixture was allowed to slowly warm up to RT and stirred at RTovernight. Then the reaction was diluted with EtOAc, washed with brine,evaporated organic solvent, the residue was purified with Combi-Flashcolumn to afford6′-bromo-7′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one. ES/MS m/z:256.00.

Intermediate 1014.6′-bromo-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-bromo-7′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one (130 mg, 051mmol) was dissolved in DMF (3 mL). To the above solution were added2,2,2-trifluoroethyl trifluoromethanesulfonate (177 mg, 0.76 mmol),potassium carbonate (140 mg, 1.02 mmol) and the reaction mixture washeated at 100° C. overnight. Then the reaction was diluted with EtOAc,washed with brine, evaporated organic solvent, the residue was purifiedwith Combi-Flash column to afford6′-bromo-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 338.00.

Intermediate 1015.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared as a racemic mixture in the manner described forIntermediate 498, but replacing 5-bromo-2-methylbenzo[d]thiazole with6′-bromo-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 451.10.

Intermediate 1016.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared in the manner described for intermediate 523,but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 555.20.

Intermediate 1017.6′-bromo-5′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one

6′-bromo-5′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one was preparedin the manner described for Intermediate 1013, but replacing6-bromo-7-fluoroindolin-2-one with 6-bromo-5-fluoroindolin-2-one. ES/MSm/z: 256.00.

Intermediate 1018.6′-bromo-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-bromo-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 1014, butreplacing 6′-bromo-7′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one with6′-bromo-5′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one. ES/MS m/z:338.00.

Intermediate 1019.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared as a racemic mixture in the manner described forIntermediate 498, but replacing 5-bromo-2-methylbenzo[d]thiazole with6′-bromo-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 451.10.

Intermediate 1020.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared in the manner described for intermediate 523,but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 555.20.

Intermediate 1021.6′-bromo-4′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one

6′-bromo-4′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one was preparedin the manner described for Intermediate 1013, but replacing6-bromo-7-fluoroindolin-2-one with 6-bromo-4-fluoroindolin-2-one. ES/MSm/z: 256.00.

Intermediate 1022.6′-bromo-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-bromo-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-onewas prepared in the manner described for Intermediate 1014, butreplacing 6′-bromo-7′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one with6′-bromo-4′-fluorospiro[cyclopropane-1,3′-indolin]-2′-one. ES/MS m/z:338.00.

Intermediate 1023.6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared as a racemic mixture in the manner described forIntermediate 498, but replacing 5-bromo-2-methylbenzo[d]thiazole with6′-bromo-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 451.10.

Intermediate 1024.6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one

6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate) was prepared in the manner described for intermediate 523,but replacing6-chloro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 555.10.

B. EXAMPLES

The following examples describe preparation of compounds of the presentinvention.

Demethylation of 2,4-Dimethoxypyrimidines Example 1.5-(8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas prepared as follows: To a solution of8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazine(54 mg, 0.17 mmol, 1 equiv) in MeOH (1.5 mL) was added 1.5 M HCl(aq)solution (1 mL). The reaction vessel was heated to 80° C. for 6 h.Solids separated were filtered, washed with water and dried affording5-(8-cyclopropyl-2-methyl-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dioneas an HCl salt. Some subsequent examples prepared in accordance withthis method were purified by HPLC in place of the aforementioned solidseparation according to standard methods. ES/MS: 284.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.71 (d, J=6.4 Hz, 1H), 11.62 (s, 1H), 8.34 (s,1H), 8.08 (d, J=6.2 Hz, 1H), 7.65 (s, 1H), 2.53 (s, 3H), 1.34-1.30 (m,2H), 1.15-1.06 (m, 2H).

Example 2.5-(8-cyclopropyl-2-phenyl-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-cyclopropyl-2-phenyl-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-phenyl-imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS m/z: 346.20 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.66-11.54 (m, 2H), 8.91 (s, 1H), 8.14-8.06(m, 2H), 8.04 (d, J=6.2 Hz, 1H), 7.52 (dd, J=8.4, 6.9 Hz, 2H), 7.48-7.37(m, 2H), 2.67 (td, J=8.4, 4.2 Hz, 1H), 1.35-1.20 (m, 4H).

Example 3. Ethyl8-cyclopropyl-6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylate

Ethyl8-cyclopropyl-6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylatewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith ethyl8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-2-carboxylate.The reaction mixture was purified by RP-HPLC (5-100% MeCN/H₂O with TFAmodifier, Gemini column) affording ethyl8-cyclopropyl-6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo-[1,2-b]pyridazine-2-carboxylateas a TFA salt. ES/MS m/z: 342.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.56 (d, J=4.9 Hz, 2H), 8.74 (s, 1H), 8.00 (d, J=6.3 Hz, 1H), 7.38 (s,1H), 4.34 (q, J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H), 1.22 (ddt, J=15.3,5.1, 2.5 Hz, 4H).

Example 4.5-(8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(methoxymethyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture) and purified by RP-HPLC (5-100% MeCN/H₂O without TFA,Gemini column). ES/MS m/z: 314.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ8.12 (s, 1H), 8.08 (d, J=1.3 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.40 (s,1H), 3.60-3.53 (m, 1H), 3.50-3.43 (m, 1H), 3.38 (s, 3H), 2.53-2.46 (m,1H), 1.90-1.81 (m, 1H), 1.42-1.34 (m, 1H), 1.30-1.22 (m, 1H).

Example 5.(S)-5-(8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(spiro[2.3]hexan-1-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (5-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 310.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.38 (d, J=2.0 Hz, 1H), 8.28 (s, 1H), 8.13 (d, J=2.0 Hz,1H), 7.65 (s, 1H), 2.56-2.44 (m, 1H), 2.42 (dd, J=8.6, 5.7 Hz, 1H),2.38-2.26 (m, 1H), 2.27-2.10 (m, 2H), 2.08-1.92 (m, 2H), 1.60 (dd,J=8.6, 5.7 Hz, 1H), 1.42 (t, J=5.7 Hz, 1H).

Example 6.5-(8-((1S,2S)-2-(tert-butyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dioneand5-(8-((1R,2R)-2-(tert-butyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dione

5-(8-((1S,2S)-2-(tert-butyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(tert-butyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (5-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 326.20 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.34-8.30 (m, 1H), 8.24 (s, 1H), 8.06-8.02(m, 1H), 7.78 (s, 1H), 2.44-2.36 (m, 1H), 1.60-1.51 (m, 1H), 1.47-1.39(m, 1H), 1.31-1.22 (m, 1H), 1.01 (s, 9H).

Example 7.5-(8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dioneand5-(8-((1R,2R)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dione

5-(8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 346.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.38 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.07(d, J=1.9 Hz, 1H), 8.01 (s, 1H), 7.38-7.22 (m, 5H), 2.74 (t, J=7.5 Hz,2H), 1.93 (tt, J=7.5, 3.7 Hz, 2H).

Example 8.5-(8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1S,2R)-[1,1′-bi(cyclopropan)]-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1R,2S)-[1,1′-bi(cyclopropan)]-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) and purified by RP-HPLC (5-100% MeCN/H₂O without TFA,Gemini column). ES/MS m/z: 310.10 [M+H]; ¹H NMR (400 MHz, Methanol-d4) δ8.14 (s, 1H), 8.06 (d, J=1.3 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.32 (s,1H), 2.43-2.34 (m, 1H), 1.63-1.52 (m, 1H), 1.28-1.21 (m, 1H), 1.15-1.10(m, 1H), 1.12-0.99 (m, 1H), 0.55-0.43 (m, 2H), 0.32-0.21 (m, 2H).

Example 9.5-(8-pyrrolidin-1-ylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-pyrrolidin-1-ylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-pyrrolidin-1-yl-imidazo[1,2-b]pyridazineand purified by filtration. ES/MS m/z: 299.20 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.61 (dd, J=6.4, 2.0 Hz, 1H), 11.49 (d, J=2.0 Hz, 1H), 8.31(d, J=1.7 Hz, 1H), 8.03 (d, J=6.2 Hz, 1H), 7.93 (s, 1H), 6.95 (s, 1H),3.79 (brs, 4H), 2.08-1.95 (m, 4H).

Example 10.5-(8-morpholinoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-morpholinoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione wasprepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]morpholineand purified by filtration. ES/MS m/z: 315.20 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.60 (dd, J=6.2, 2.0 Hz, 1H), 11.52 (d, J=2.0 Hz, 1H), 8.26(d, J=1.5 Hz, 1H), 8.02 (d, J=6.2 Hz, 1H), 7.83 (s, 1H), 7.18 (s, 1H),3.85-3.73 (m, 8H).

Example 11.5-(8-imidazol-1-ylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-imidazol-1-ylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-imidazol-1-yl-imidazo[1,2-b]pyridazineand purified by filtration. ES/MS m/z: 296.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.82 (dd, J=6.3, 2.0 Hz, 1H), 11.67 (d, J=1.9 Hz, 1H), 10.06(t, J=1.4 Hz, 1H), 8.66 (t, J=1.8 Hz, 1H), 8.55 (d, J=1.3 Hz, 1H), 8.24(s, 1H), 8.14 (d, J=6.2 Hz, 1H), 7.96 (d, J=1.3 Hz, 1H), 7.90 (dd,J=2.0, 1.2 Hz, 1H).

Example 12.5-(8-(benzylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(benzylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewithN-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-amine(41 mg, 0.113 mmol, 1 equiv) to provide the title compound. Theresultant compound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA).ES/MS m/z: 335.1 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.52-11.40 (m, 2H),8.18 (dd, J=8.0, 3.9 Hz, 2H), 7.97 (d, J=6.1 Hz, 1H), 7.79 (s, 1H),7.44-7.38 (m, 2H), 7.38-7.31 (m, 2H), 7.31-7.23 (m, 1H), 6.99 (s, 1H),4.56 (d, J=5.9 Hz, 2H).

Example 13.5-(8-(benzyl(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(benzyl(methyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewithN-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)-N-methylimidazo[1,2-b]pyridazin-8-amine(90 mg, 0.239 mmol, 1 equiv) to provide the title compound. Theresultant compound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA).ES/MS m/z: 349.1 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (d, J=6.6 Hz,2H), 8.05 (d, J=1.2 Hz, 1H), 7.96 (d, J=6.0 Hz, 1H), 7.56 (d, J=1.2 Hz,1H), 7.35-7.27 (m, 2H), 7.27-7.20 (m, 3H), 6.80 (s, 1H), 5.55 (s, 2H),3.14 (s, 3H).

Example 14.5-(8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4,4-difluorocyclohexyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(20 mg, 0.053 mmol, 1 equiv) to provide the title compound. Theresultant compound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA).ES/MS m/z: 348.1 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63 (dd, J=6.2,2.0 Hz, 1H), 11.59 (d, J=2.0 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.07 (d,J=6.2 Hz, 1H), 8.04-7.96 (m, 1H), 7.81 (s, 1H), 3.39-3.27 (m, 1H),2.25-1.95 (m, 6H), 1.87 (dt, J=14.5, 11.1 Hz, 2H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.13 (s, 3F), −89.97 (d, J=233.5 Hz, 1F), −99.92-−101.11(m, 1F).

Example 15.5-(8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-isopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazine(53 mg, mmol, 1 equiv) to provide the title compound. The resultantcompound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA). ES/MSm/z: 340.1 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.61 (d, J=1.9 Hz, 1H),11.59 (s, 1H), 8.90 (d, J=1.0 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.76 (s,1H), 3.51 (p, J=6.9 Hz, 1H), 1.36 (d, J=6.9 Hz, 6H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −61.57 (s, 3F).

Example 16.5-(8-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith 6-(2,4-dimethoxypyrimidin-(60 mg, 0.198 mmol, 1 equiv) to providethe title compound. The resultant compound was purified by HPLC (10-90%MeCN/H₂O with 0.1% TFA). ES/MS m/z: 273.1 [M+1]. ¹H NMR (400 MHz,DMSO-d6) δ 11.64-11.58 (m, 1H), 11.57 (d, J=2.0 Hz, 1H), 9.59 (s, 1H),8.05 (d, J=6.2 Hz, 1H), 7.65 (d, J=0.9 Hz, 1H), 3.52-3.45 (m, 2H), 1.41(d, J=6.9 Hz, 6H).

Example 17.5-(8-benzylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-benzylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione wasprepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith 8-benzyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(16 mg, 0.046 mmol, 1 equiv) to provide the title compound. Theresultant compound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA).ES/MS m/z: 320.1 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.59-11.53 (m, 1H),11.51 (d, J=2.0 Hz, 1H), 8.37 (d, J=1.4 Hz, 1H), 8.01 (d, J=6.2 Hz, 1H),7.94 (d, J=10.9 Hz, 1H), 7.64 (s, 1H), 7.44-7.35 (m, 2H), 7.31 (dd,J=8.3, 6.6 Hz, 2H), 7.27-7.19 (m, 1H), 4.34 (s, 2H).

Example 18.5-[8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine(5 mg, mmol, 1 equiv) to provide the title compound. The resultantcompound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA). ES/MSm/z: 338.1 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (d, J=10.0 Hz, 2H),8.35 (s, 1H), 8.07 (d, J=6.1 Hz, 1H), 7.95 (s, 1H), 7.84 (s, 1H),1.60-1.52 (m, 2H), 1.49 (d, J=12.1 Hz, 2H).

Example 19.5-[2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-2,8-bis[1-(trifluoromethyl)cyclopropyl]imidazo[1,2-b]pyridazine(12 mg, 0.025 mmol, 1 equiv) to provide the title compound. Theresultant compound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA).ES/MS m/z: 446.1 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (d, J=2.0 Hz,1H), 11.54 (dd, J=6.3, 2.0 Hz, 1H), 8.03 (s, 1H), 8.01 (d, J=6.3 Hz,1H), 7.93 (s, 1H), 1.55 (td, J=7.5, 5.1 Hz, 4H), 1.48-1.36 (m, 4H).

Example 20.5-[8-(benzenesulfonylmethyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-(benzenesulfonylmethyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(benzenesulfonylmethyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(22 mg, 0.054 mmol, 1 equiv) to provide the title compound. Theresultant compound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA).ES/MS m/z: 384.0 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.71-11.63 (m, 1H),11.57 (d, J=2.0 Hz, 1H), 8.09 (d, J=9.7 Hz, 1H), 7.98 (d, J=6.2 Hz, 1H),7.88 (d, J=9.6 Hz, 1H), 7.69 (s, 1H), 7.64-7.55 (m, 3H), 7.45 (t, J=7.6Hz, 2H), 5.27 (s, 2H).

Example 21.5-[2,8-bis(benzenesulfonylmethyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[2,8-bis(benzenesulfonylmethyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2,8-bis(benzenesulfonylmethyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]-pyridazine(4 mg, mmol, 1 equiv) to provide the title compound. The resultantcompound was purified by HPLC (10-90% MeCN/H₂O with 0.1% TFA). ES/MSm/z: 538.1 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.67 (d, J=6.0 Hz, 1H),11.55 (s, 1H), 7.96 (d, J=6.3 Hz, 1H), 7.84 (s, 1H), 7.79-7.74 (m, 2H),7.73-7.66 (m, 1H), 7.62-7.51 (m, 5H), 7.49-7.41 (m, 3H), 5.21 (s, 2H),5.08 (s, 2H).

Example 22.5-(8-cyclopropylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a solution of8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(22 mg, 0.07 mmol, 1 equiv) in MeOH (1 mL) was added 1M HCl aqueoussolution (1 mL). The vessel was sealed and heated to 70° C. for 16 h.Purification was accomplished by reverse phase HPLC (10-90% MeCN/H₂Owith 0.1% TFA) affording 5-(8-cyclopropylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione as a TFA salt. ES/MS: 270.10 [M+1]. ¹H NMR(400 MHz, DMSO-d₆) δ 11.68-11.28 (m, 2H), 8.33 (s, 1H), 8.01 (d, J=6.2Hz, 1H), 7.89 (s, 1H), 7.45 (s, 1H), 2.47-2.42 (m, 1H), 1.27-1.15 (m,4H).

Example 23. 5-(imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (66 mg, 0.26mmol was dissolved in MeOH (1 ML). To the reaction mixture was added 1Naqueous HCl (1 mL). The reaction mixture was then heated at 50° C. for 2h. The reaction mixture was then neutralized with NaHCO₃ and evaporated.The residue was washed with MeOH and water to afford5-(imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione. ES/MS m/z:230.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.41 (s, 1H),8.13 (d, J=9.7 Hz, 1H), 8.09 (s, 1H), 7.85 (d, J=9.7 Hz, 1H), 7.58 (d,J=1.1 Hz, 1H).

Example 24.5-(8-cyclopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

8-cyclopropoxy-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(87 mg, mmol was dissolved in MeOH (2 mL). To the reaction mixture wasadded aqueous 1N HCl (1 mL). The reaction mixture was then heated at 50°C. for 2 h. The reaction mixture was then neutralized with NaHCO₃ andevaporated. The residue was washed with MeOH and water to afford5-(8-cyclopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 286.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.43(s, 1H), 8.09-7.99 (m, 2H), 7.44 (d, J=1.1 Hz, 1H), 4.08 (tt, J=6.2, 3.0Hz, 1H), 0.94-0.78 (m, 4H).

Example 25.5-(8-isopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

A solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-isopropoxyimidazo[1,2-b]pyridazine (70mg, 0.22 mmol, 1 equiv) in 1:1 1N HCl/MeOH (2.5 mL) was heated at 70° C.After 6 hours, the reaction mixture was purified by RP-HPLC (5-80%MeCN/H₂O with TFA modifier, Gemini column), affording5-(8-isopropoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 288.10 [M+H]; ¹H NMR (400 MHz, Methanol-d4) δ 8.34 (d, J=2.0Hz, 1H), 8.33 (s, 1H), 8.02 (d, J=2.0 Hz, 1H), 7.95 (s, 1H), 5.19-5.08(m, 1H), 1.58 (d, J=6.1 Hz, 6H).

Example 26.5-(8-benzylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

8-benzyloxy-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (41mg, 0.113 mmol), MeOH (0.5 mL), and 1 M HCl (0.45 mL) were combined andheated to 50° C. overnight. The mixture was diluted with DMF/H₂O andpurified by reverse-phase HPLC (10-90% MeCN/H₂O with 0.1% TFA). ES/MSm/z: 336.1 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 11.68-11.46 (m, 2H), 8.30(s, 1H), 8.07 (d, J=6.1 Hz, 1H), 7.79 (s, 1H), 7.60-7.51 (m, 3H),7.48-7.36 (m, 3H), 5.45 (s, 2H).

Example 27.5-(7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

a) A microwave vial was charged with5,7-dichloropyrazolo[1,5-a]pyrimidine (100 mg, 0.53 mmol, 1 equiv),cyclopropylboronic acid (69 mg, 0.80 mmol, 1.5 equiv), cesium carbonate(347 mg, 1.1 mmol, 2 equiv), and Pd(dppf)Cl₂·CH₂Cl₂ (39 mg, 10 mol %).The reaction mixture was dissolved in 2:1 dioxane/H₂O (2 mL), purgedwith argon, and microwaved at 120° C. After 1 hour, the reaction mixturewas directly purified by SiO₂ chromatography (0-30% MeOH/CH₂Cl₂),affording 5-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine. ES/MS m/z:194.10 [M+H]; ¹H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J=2.3 Hz, 1H), 6.81(s, 1H), 6.70 (d, J=2.3 Hz, 1H), 2.86-2.77 (m, 1H), 1.35-1.22 (m, 4H).

(b) A microwave vial was charged with5-chloro-7-cyclopropylpyrazolo[1,5-a]pyrimidine (27 mg, 0.14 mmol, 1equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (39 mg, mmol, 1.5equiv), cesium carbonate (91 mg, 0.28 mmol, 2 equiv), andPd(dppf)Cl₂—CH₂Cl₂ (10 mg, 10 mol %). The reaction mixture was dissolvedin 2:1 dioxane/H₂O (2 mL), purged with argon, and heated at 80° C. After30 minutes, the reaction mixture was directly purified by SiO₂chromatography (0-30% MeOH/CH₂Cl₂), affording7-cyclopropyl-5-(2,4-dimethoxypyrimidin-ES/MS m/z: 298.20 [M+H]; ¹H NMR(400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.07 (s, 1H),6.75 (d, J=2.3 Hz, 1H), 4.04 (s, 3H), 3.98 (s, 3H), 2.89-2.78 (m, 1H),1.36-1.12 (m, 4H).

(c) A solution of7-cyclopropyl-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine(38 mg, 0.13 mmol, 1 equiv) in 1:1 1N HCl/MeOH (1.5 mL) was heated at50° C. After 14 hours, the reaction mixture was purified by RP-HPLC(10-90% MeCN/H₂O with TFA modifier, Gemini column), affording5-(7-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 270.10 [M+H]; ¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.57 (m,1H), 11.50 (s, 1H), 8.32 (d, J=6.3 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.51(s, 1H), 6.62 (d, J=2.3 Hz, 1H), 2.85-2.74 (m, 1H), 1.34-1.27 (m, 2H),1.10-1.03 (m, 2H).

Example 41.5-[8-[(1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(1R,2R)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-[3-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture) and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 414.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ8.39-8.38 (m, 1H), 8.31-8.30 (m, 1H), 8.11-8.02 (m, 2H), 7.64-7.53 (m,4H), 2.89-2.80 (m, 2H), 1.99-1.96 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −64.67 (s, 3F), −77.72 (s, 3F).

Example 42.5-[8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(1R,2R)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture) and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 414.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ8.40 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.12-8.04 (m, 2H), 7.69-7.62 (m,2H), 7.49-7.47 (m, 2H), 2.85-2.81 (m, 2H), 2.03-1.96 (td, J=7.4, 2.1 Hz,2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −64.47 (s, 3F), −77.75 (s, 3F).

Example 45.5-(8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(4-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-cyclopropylphenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 386.10 [M+H]. ¹HNMR (400 MHz, Acetonitrile-d3) δ 7.06 (d, J=2.1 Hz, 1H), 6.96 (s, 1H),6.77 (d, J=2.1 Hz, 1H), 6.72 (s, 1H), 5.87-5.76 (m, 2H), 5.75-5.64 (m,2H), 1.40-1.18 (m, 2H), 0.67-0.43 (m, 3H), −0.34-−0.52 (m, 2H),−0.60-−0.81 (m, 2H).

Example 47.5-(8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione and5-(8-((1R,2R)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione was prepared as a racemic mixture in themanner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 430.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.37 (d, J=1.9 Hz, 1H), 8.29 (s, 1H), 8.06(d, J=1.9 Hz, 1H), 8.00 (s, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.30 (dt,J=7.9, 1.3 Hz, 1H), 7.22 (s, 1H), 7.18 (ddt, J=8.0, 2.3, 1.1 Hz, 1H),2.81 (ddt, J=9.0, 6.4, 3.5 Hz, 2H), 2.04-1.86 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −59.86 (s, 3F), −77.69 (s, 3F).

Example 48.5-(8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 430.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.38 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.07(d, J=1.9 Hz, 1H), 8.02 (s, 1H), 7.46-7.34 (m, 2H), 7.27 (d, J=8.2 Hz,2H), 2.89-2.70 (m, 2H), 2.01-1.86 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −60.15 (s, 3F), −77.77 (s, 3F).

Example 52.5-[8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(1R,2R)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) and isolated by filtration as an HCl salt aftertrituration with acetonitrile and ethylacetate. ES/MS m/z: 347.10 [M+H].¹H NMR (400 MHz, DMSO-d6) δ 11.78-11.76 (m, 1H), 11.64-11.63 (m, 1H),8.69-8.67 (m, 1H), 8.56-8.55 (m, 1H), 8.24-8.14 (m, 2H), 8.13-8.11 (m,1H), 7.88 (s, 1H), 7.76-7.74 (m, 1H), 7.64-7.61 (m, 1H), 3.25-3.21 (m,1H), 3.13-3.10 (m, 1H), 2.23-2.11 (m, 2H).

Example 53.5-[8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(1R,2R)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) and purified by RP-HPLC (5-70% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 347.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ8.84-8.83 (m, 1H), 8.74-8.67 (m, 1H), 8.42-8.39 (m, 1H), 8.37-8.24 (m,2H), 7.98-7.95 (m, 3H), 3.03-2.91 (m, 2H), 2.17-2.12 (m, 1H), 2.06-2.01(m, 1H).

Example 54.5-[8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(1R,2R)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) and purified by RP-HPLC (5-70% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 347.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4)8.75-8.73 (m, 2H), 8.31-8.27 (m, 2H), 7.96-7.94 (m, 4H), 3.23-3.18 (m,1H), 3.05-3.01 (m, 1H), 2.38-2.32 (m, 1H), 2.18-2.13 (m, 1H).

Example 55.5-(8-(4,4-difluorocyclohexyl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4,4-difluorocyclohexyl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 363.1 [M+1]. ¹H NMR (400 MHz,DMSO-d6) δ 11.60 (d, J=3.9 Hz, 2H), 8.09 (d, J=6.5 Hz, 1H), 7.97 (s,1H), 3.31-3.24 (m, 1H), 2.53 (s, 3H), 2.20-1.86 (m, 8H). ¹⁹F NMR (376MHz, DMSO-d6) δ −90.03 (d, J=233.5 Hz, 1F), −99.94 (m, 1F).

Example 56.8-(4,4-difluorocyclohexyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile

8-(4,4-difluorocyclohexyl)-6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine-3-carbonitrile.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 373.1 [M+1]. ¹H NMR (400 MHz,DMSO-d6) δ 11.64 (d, J=6.8 Hz, 2H), 8.55 (s, 1H), 8.12 (d, J=6.1 Hz,1H), 7.94 (s, 1H), 3.32-3.23 (m, 1H), 2.24-1.86 (m, 8H). ¹⁹F NMR (376MHz, DMSO-d6) δ −90.04 (d, J=233.4 Hz, 1F), −101.02 (m, 1F).

Example 57.5-(8-(4,4-difluorocyclohexyl)-3-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4,4-difluorocyclohexyl)-3-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(4,4-difluorocyclohexyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 362.1 [M+1]. ¹H NMR (400 MHz,DMSO-d6) δ 11.67 (d, J=6.3 Hz, 1H), 11.61 (d, J=2.0 Hz, 1H), 8.19 (d,J=6.2 Hz, 1H), 7.90 (s, 2H), 3.32 (t, J=12.1 Hz, 2H), 2.55 (d, J=1.0 Hz,3H), 2.26-2.13 (m, 2H), 2.13-2.03 (m, 3H), 2.03-1.93 (m, 1H), 1.93-1.78(m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.95 (s, 3F), −90.00 (d, J=233.9Hz, 1F), —99.99 (m, 1F).

Example 58.5-(8-((benzyloxy)methyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((benzyloxy)methyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((benzyloxy)methyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 350.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.64 (dd, J=6.2, 2.0 Hz, 1H), 11.60 (d, J=2.0 Hz, 1H), 8.42(d, J=1.5 Hz, 1H), 8.09 (d, J=6.2 Hz, 1H), 8.04 (s, 1H), 7.95 (d, J=1.5Hz, 1H), 7.46-7.41 (m, 2H), 7.41-7.35 (m, 2H), 7.35-7.28 (m, 1H), 4.96(s, 2H), 4.72 (s, 2H).

Example 59.5-(8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine,and running the reaction at 70° C. for 4 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 361.1 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.47-11.33(m, 2H), 8.07 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.61 (s, 1H),7.47-7.41 (m, 2H), 7.38 (dd, J=8.4, 6.8 Hz, 2H), 7.31-7.25 (m, 1H), 6.54(s, 1H), 4.87-4.74 (m, 2H), 4.41-4.31 (m, 2H), 4.11 (tt, J=8.6, 6.1 Hz,1H).

Example 60.5-(8-((1S,2S)-2-(3,5-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(3,5-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3,5-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 382.1 [M+1]. ¹HNMR (400 MHz, DMSO-d6) δ 11.52 (d, J=4.1 Hz, 2H), 8.30 (d, J=1.3 Hz,1H), 8.01 (d, J=6.4 Hz, 1H), 7.81 (s, 1H), 7.54 (s, 1H), 7.05 (td,J=8.2, 7.4, 3.2 Hz, 3H), 2.88 (dt, J=9.3, 5.5 Hz, 1H), 2.77 (ddd, J=8.8,6.1, 4.3 Hz, 1H), 2.14 (dt, J=8.7, 5.4 Hz, 1H), 1.81 (dt, J=8.7, 5.3 Hz,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.90 (m, 3F), −110.76 (dd, J=10.3,7.6 Hz, 2F).

Example 61.5-(8-((1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(2,3,5-trifluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2,3,5-trifluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(2,3,5-trifluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile(racemic mixture). Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 389.1 [M+1]. ¹HNMR (400 MHz, DMSO-d6) δ 11.54 (d, J=3.7 Hz, 2H), 8.31 (d, J=1.4 Hz,1H), 8.02 (d, J=6.4 Hz, 1H), 7.88-7.79 (m, 2H), 7.58 (s, 1H), 7.47 (dd,J=11.1, 1.5 Hz, 1H), 7.34 (dd, J=8.2, 1.6 Hz, 1H), 2.96 (dd, J=8.8, 5.1Hz, 1H), 2.86 (ddd, J=8.9, 6.2, 4.4 Hz, 1H), 2.24 (dt, J=8.7, 5.4 Hz,1H), 1.89 (dt, J=8.8, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.04(s, 3F), −109.50 (dd, J=11.0, 7.2 Hz, 1F).

Example 62.5-(8-(3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(trifluoromethyl)azetidin-1-yl]imidazo[1,2-b]pyridazine,and running the reaction at 70° C. for 4 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 353.1 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43 (dt,J=6.1, 2.0 Hz, 2H), 8.09 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.62(d, J=1.3 Hz, 1H), 6.53 (s, 1H), 4.62 (t, J=9.2 Hz, 2H), 4.41-4.33 (m,2H), 3.83 (dh, J=14.1, 5.0 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −72.74(d, J=9.3 Hz, 3F), −75.39 (s, 3F).

Example 63.5-(8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylazetidin-1-yl)imidazo[1,2-b]pyridazine,and running the reaction at 70° C. for 4 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 313.2 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.42 (d,J=6.7 Hz, 2H), 8.09 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.64 (d,J=1.3 Hz, 1H), 6.50 (s, 1H), 4.10-4.03 (m, 4H), 1.32 (s, 6H).

Example 64.5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrileand5-((1R,2R)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrilewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile(racemic mixture). Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 389.1 [M+1]. ¹HNMR (400 MHz, DMSO-d6) δ 11.59 (d, J=7.5 Hz, 2H), 8.37 (d, J=1.5 Hz,1H), 8.04 (d, J=6.0 Hz, 1H), 7.91 (s, 1H), 7.85 (dd, J=6.1, 2.4 Hz, 1H),7.71 (ddd, J=7.9, 5.2, 2.4 Hz, 1H), 7.60 (s, 1H), 7.49 (t, J=9.0 Hz,1H), 2.88 (ddd, J=9.3, 6.2, 4.4 Hz, 1H), 2.81-2.73 (m, 1H), 2.10 (dt,J=9.0, 5.4 Hz, 1H), 1.85 (dt, J=8.6, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.13 (s, 3F), −113.01 (q, J=6.2 Hz, 1F).

Example 65.5-(8-((1S,2S)-2-(2,5-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(2,5-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2,5-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-(2,5-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z:

Example 66.5-(8-(2-phenylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-(2-phenylazetidin-1-yl)imidazo[1,2-b]pyridazine(50 mg, 0.129 mmol) in MeCN (3 mL) was added iodotrimethylsilane (0.183mL, 1.29 mmol). The mixture was stirred at rt for 3 h, then concentratedin vacuo. The resulting residue was diluted with THF (2.5 mL), andpotassium tert-butoxide (58 mg, 0.516 mmol) was added. The mixture washeated to 70° C. for 1 h. The mixture was then quenched with water, anddiluted with water/MeCN. Purification was accomplished by RP-HPLC(10-90% MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 361.1[M+1]. ¹H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H), 8.23 (d, J=2.3 Hz,1H), 7.70 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.46-7.39 (m, 3H), 7.26-7.22(m, 2H), 5.87 (dd, J=7.4, 3.7 Hz, 1H), 3.61-3.51 (m, 2H), 2.75-2.65 (m,2H).

Example 67.5-[8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as follows: To a solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine(93 mg, 0.22 mmol, 1 equiv) in MeOH (2.5 mL) was added 1 M HCl(aq)solution (1.5 mL). The reaction vessel was heated to 80° C. for 6 h.Solids separated were filtered, washed with water and dried affording5-[8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneas an HCl salt. Some subsequent examples prepared in accordance withthis method were purified by HPLC in place of the aforementioned solidseparation according to standard methods. ES/MS: 393.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.58-11.51 (m, 1H), 11.46-11.45 (m, 1H), 8.26-8.25(m, 1H), 8.03-8.01 (m, 1H), 7.86 (s, 1H), 7.50-7.40 (m, 2H), 7.25-7.14(m, 2H), 6.92 (s, 1H), 4.38 (brs, 1H), 4.00 (brs, 1H), 3.82 (brs, 2H),3.68-3.56 (m, 1H), 2.45-2.42 (m, 1H), 2.22-2.07 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −116.67 (m, 1F).

Example 68.5-[8-[(3S)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(3S)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3S)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 393.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.56-11.54 (m, 1H), 11.46-11.45 (m, 1H), 8.27-8.26(m, 1H), 8.03-8.01 (m, 1H), 7.87 (s, 1H), 7.47-7.43 (m, 2H), 7.22-7.17(m, 2H), 6.92 (s, 1H), 4.38 (brs, 1H), 3.96 (brs, 1H), 3.81 (brs, 2H),3.68-3.56 (m, 1H), 2.47-2.42 (m, 1H), 2.19-2.09 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −116.67 (m, 1F).

Example 69.5-(8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine.The reaction mixture was purified by RP-HPLC (5-100% MeCN/H₂O with TFAmodifier, Gemini column) affording5-(8-cyclopropyl-3-fluoro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dioneas a TFA salt. ES/MS m/z: 288.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.60-11.58 (m, 1H), 11.53-11.52 (m, 1H), 8.03-8.02 (m, 1H), 7.68-7.66(m, 1H), 7.40 (s, 1H), 2.51-2.42 (m, 1H), 1.26-1.23 (m, 4H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −155.46 (d, J=6.9 Hz, 1F).

Example 70.5-[8-(4,4-difluoro-1-piperidyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-(4,4-difluoro-1-piperidyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-(4,4-difluoro-1-piperidyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 349.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.55-11.54 (m, 1H), 11.48-11.47 (m, 1H), 8.22-8.21(m, 1H), 8.01-7.97 (m, 1H), 7.80-7.75 (m, 1H), 7.18 (s, 1H), 4.00-3.98(m, 4H), 2.22-2.12 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −95.83 (m, 2F).

Example 71.5-[8-[4-(cyclopropylmethylamino)phenyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[4-(cyclopropylmethylamino)phenyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewithN-(cyclopropylmethyl)-4-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]anilineand isolated by filtration as an HCl salt. ES/MS: 375.20 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.84-11.82 (m, 1H), 11.63-11.62 (m, 1H), 8.61-8.60(m, 1H), 8.28-8.08 (m, 3H), 7.87-7.85 (m, 2H), 6.98-6.96 (m, 2H),3.07-3.06 (m, 2H), 1.18-1.06 (m, 1H), 0.56-0.47 (m, 2H), 0.35-0.22 (m,2H).

Example 72.5-[8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (5-100% MeCN/H₂O with TFA, Gemini column).ES/MS: 327.20 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43-11.40 (m, 2H),8.09-8.08 (m, 1H), 7.95-7.94 (m, 1H), 7.63-7.62 (m, 1H), 6.63 (s, 1H),3.84-3.68 (m, 4H), 1.85-1.77 (m, 2H), 1.13 (s, 6H).

Example 73.5-[8-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(3R,4R)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-[(3S,4S)-3,4-difluoropyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) and isolated by filtration as an HCl salt. ES/MS m/z:335.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.59-11.57 (m, 1H),11.47-1.46 (m, 1H), 8.28-8.23 (m, 1H), 8.03-8.01 (m, 1H), 7.83-7.82 (m,1H), 6.89 (s, 1H), 5.71-5.45 (m, 2H), 4.41-4.05 (m, 4H). ¹⁹F NMR (377MHz, DMSO-d6) δ −188.83 (m, 2F).

Example 74.5-[8-[(1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(1R,2R)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(1-naphthyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) and purified by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 396.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ8.46-8.45 (m, 1H), 8.36 (s, 1H), 8.24 (s, 1H), 8.16-8.08 (m, 2H),7.96-7.88 (m, 1H), 7.85-7.83 m, 1H), 7.56-7.42 (m, 4H), 3.30-3.26 (m,1H), 2.68-2.63 (m, 1H), 2.17-2.11 (m, 1H), 2.08-1.93 (m, 1H).

Example 75.5-(2,8-dicyclopropylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(2,8-dicyclopropylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith2,8-dicyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (5-90% MeCN/H₂O with TFA, Gemini column). ES/MS:310.20 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62-11.55 (m, 2H), 8.27 (s,1H), 8.02-8.01 (m, 1H), 7.53 (s, 1H), 2.58-2.51 (m, 1H), 2.20-2.08 (m,1H), 1.34-1.22 (m, 2H), 1.17-1.08 (m, 4H), 1.05-0.93 (m, 2H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.35.

Example 76.5-[3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[3-fluoro-8-[(1R,2R)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(Racemic Mixture) and isolated by filtration as an HCl salt. ES/MS m/z:382.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.61 (m, 1H),11.55-1.54 (m, 1H), 8.05-8.04 (m, 1H), 7.66-7.64 (m, 1H), 7.51 (s, 1H),7.36-7.25 (m, 2H), 7.19-7.08 (m, 2H), 2.85-2.80 (m, 1H), 2.73-2.68 (m,1H), 2.06-2.01 (m, 1H), 1.77-1.72 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−117.32 (m, 1F), −155.36 (d, J=7.1 Hz, 1F).

Example 77.5-[8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[8-[(3R,4S)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(meso) and isolated by filtration as an HCl salt. ES/MS m/z: 335.10[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.59-11.57 (m, 1H), 11.46-11.45 (m,1H), 8.25-8.22 (m, 1H), 8.02-7.97 (m, 1H), 7.83-7.82 (m, 1H), 6.86 (s,1H), 5.64-5.40 (m, 2H), 4.37-3.95 (m, 4H). ¹⁹F NMR (377 MHz, DMSO-d6) δ−205.69 (m, 2F).

Example 78.5-(8-pyrazol-1-ylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione

5-(8-pyrazol-1-ylimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-pyrazol-1-yl-imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 296.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.63-11.61 (m, 2H), 9.58-9.57 (m, 1H), 8.48-8.37(m, 2H), 8.14-8.11 (m, 1H), 8.04-8.03 (m, 1H), 7.91-7.88 (m, 1H),6.75-6.74 (m, 1H).

Example 79.5-[8-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-(3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-(3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 335.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.57-11.43 (m, 2H), 8.18-8.17 (m, 1H), 7.99-7.96(m, 1H), 7.73-7.71 (m, 1H), 6.77 (s, 1H), 4.40-4.37 (m, 2H), 4.00-3.96(m, 2H), 2.67-2.56 (m, 2H). ¹⁹F NMR (377 MHz, DMSO-d6) δ −101.14 (m,2F).

Example 80.5-[8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 363.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.58-11.46 (m, 2H), 8.23-8.22 (m, 1H), 8.01-7.97(m, 1H), 7.81-7.80 (m, 1H), 6.81 (s, 1H), 4.47-4.41 (m, 2H), 3.83-3.82(m, 2H), 1.22-1.20 (m, 6H). ¹⁹F NMR (377 MHz, DMSO-d6) δ −115.19 (m,2F).

Example 81.5-[8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 381.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.50-11.36 (m, 2H), 7.98-7.96 (m, 1H), 7.42-7.40(m, 1H), 6.59-6.58 (m, 1H), 4.40 (brs, 2H), 3.85 (brs, 2H), 1.21 (s,6H). ¹⁹F NMR (377 MHz, DMSO-d6) δ −115.42 (m, 2F), −155.50 (d, J=7.4 Hz,1F).

Example 82.5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

A solution of8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-(377mg) in 1:1 1N HCl/MeOH (5 mL) was heated to ° C. After 20 hours, thereaction mixture was filtered. The resulting solids were washed withMeCN (10 mL) and dried under reduced pressure to afford thehydrochloride salt of5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, Methanol-d4) δ 8.13 (s, 1H), 7.24 (d, J=7.1 Hz, 1H),6.70 (s, 1H), 4.56 (t, J=12.5 Hz, 2H), 4.06 (s, 2H), 1.19-1.14 (m, 2H),1.01-0.91 (m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −111.24 (t, J=12.4Hz, 2F), −157.79 (d, J=7.4 Hz, 1F). ES/MS m/z: 379.10 [M+H].

Example 83.5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

A solution of8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-(55mg) in 1:1 1N HCl/MeOH (2 mL) was heated to 80 C. After 14 hours, thesolvent was evaporated and purified with Prep HPLC to afford5-(8-(7,7-difluoro-trifluoroacetic acid salt. ES/MS m/z: 361.10 [M+H].¹H NMR (400 MHz, DMSO-d6) δ 11.40 (dd, J=9.5, 4.1 Hz, 2H), 8.08 (d,J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.1 Hz, 1H), 6.61 (s,1H), 4.57 (t, J=12.4 Hz, 2H), 4.02 (s, 2H), 1.10-0.96 (m, 4H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.28 (s, 3F), −107.45 (t, J=12.6 Hz, 2F).

Example 84.5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 67, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 362.1 [M+1]. ¹H NMR (400 MHz,DMSO-d6) δ 11.48 (d, J=3.6 Hz, 2H), 8.45 (s, 1H), 8.06 (d, J=6.4 Hz,1H), 7.00 (s, 1H), 4.53 (s, 2H), 4.03 (s, 2H), 1.12-0.91 (m, 4H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −107.36 (t, J=12.6 Hz, 2F).

Example 85.3-[(1S,2S)-2-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-fluoro-benzonitrileand3-[(1R,2R)-2-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-fluoro-benzonitrile

3-[(1S,2S)-2-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-fluoro-benzonitrilewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith3-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-fluoro-benzonitrile(racemic mixture) and isolated by filtration as an HCl salt. ES/MS m/z:389.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.78-11.74 (m, 1H),11.63-11.62 (m, 1H), 8.57-8.56 (m, 1H), 8.22 (s, 1H), 8.12-8.11 (m, 1H),7.81 (s, 1H), 7.75-7.65 (m, 2H), 7.60-7.57 (m, 1H), 3.13-3.03 (m, 1H),2.87-2.82 (m, 1H), 2.06-1.95 (m, 2H). ¹⁹F NMR (377 MHz, DMSO-d6) δ−111.39 (m, 1F).

Example 86.5-[2-cyclopropyl-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[2-cyclopropyl-8-[(1R,2R)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[2-cyclopropyl-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith2-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) and isolated by filtration as an HCl salt. ES/MS m/z:404.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.74-11.73 (m, 1H),11.60-11.59 (m, 1H), 8.34 (s, 1H), 8.07-8.06 (m, 1H), 7.72 (s, 1H),7.39-7.29 (m, 2H), 7.22-7.11 (m, 2H), 3.03-3.02 (m, 1H), 2.76-2.71 (m,1H), 2.22-2.15 (m, 1H), 1.83-1.80 (m, 2H), 1.15-1.10 (m, 2H), 1.06-1.00(m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −117.27 (m, 1F).

Example 87.5-[3-fluoro-8-[(1S,2S)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dioneand5-[3-fluoro-8-[(1R,2R)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[3-fluoro-8-[(1S,2S)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared as a racemic mixture in the manner described for Example67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-phenylcyclopropyl]imidazo[1,2-b]pyridazine(racemic mixture) and purified by RP-HPLC (5-100% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 364.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.53-11.52 (m, 2H), 8.04-8.02 (m, 1H), 7.55-7.50 (m, 1H), 7.46 (s, 1H),7.36-7.13 (m, 5H), 2.84-2.79 (m, 1H), 2.74-2.64 (m, 1H), 2.13-2.03 (m,1H), 1.78-1.73 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.87 (s, 3F),−155.60 (d, J=7.0 Hz, 1F).

Example 88.5-[8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 400.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.64-11.48 (m, 2H), 8.06-8.02 (m, 1H), 7.63-7.61(m, 1H), 7.55 (s, 1H), 7.36-7.32 (m, 1H), 7.25-7.19 (m, 1H), 7.14-7.04(m, 1H), 3.02-2.92 (m, 1H), 2.79-2.66 (m, 1H), 2.13-2.05 (m, 1H),1.82-1.77 (m, 1H). ¹⁹F NMR (377 MHz, DMSO-d6) δ −113.39 (m, 1F), −115.89(m, 1F), −155.44 (d, J=7.1 Hz, 1F).

Example 89.5-[8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(4,4-dimethyl-1-piperidyl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 341.20 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.61-11.54 (m, 1H), 11.48-11.47 (m, 1H), 8.48-8.47(m, 2H), 8.24-8.23 (m, 1H), 8.03-8.01 (m, 1H), 7.86-7.81 (m, 1H), 7.22(s, 1H), 3.82-3.74 (m, 4H), 2.08 (s, OH), 1.54-1.46 (m, 4H), 1.01 (s,6H).

Example 90.5-[8-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-(3,4-difluorophenyl)cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 67, but replacing6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(4-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-6-(3,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS: 400.10 [M+1]. ¹H NMR(400 MHz, DMSO-d6) δ 11.56-11.54 (s, 2H), 8.04-8.02 (m, 1H), 7.56-7.53(m, 1H), 7.48 (s, 1H), 7.42-7.29 (m, 2H), 7.18-7.09 (m, 1H), 2.89-2.84(m, 1H), 2.71-2.67 (m, 1H), 2.13-2.08 (m, 1H), 1.78-1.73 (m, 1H). ¹⁹FNMR (377 MHz, DMSO-d6) δ −139.37 (m, 1F), −142.87 (m, 1F), −155.62 (d,J=7.0 Hz, 1F).

Example 91.5-(7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 327.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H),11.82 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 6.71 (s,1H), 6.53 (s, 1H), 3.98 (m, 4H), 1.90-1.78 (m, 2H), 1.14 (s, 6H).

Example 92.5-(7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 328.13 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.66 (dd, J=6.4, 2.0 Hz, 1H), 11.53 (d, J=1.9 Hz, 1H),8.53-8.39 (m, 2H), 7.41 (s, 1H), 3.87-3.55 (m, 4H), 1.82 (t, J=7.1 Hz,2H), 1.13 (s, 6H).

Example 93.5-(8-(3,3-difluoropiperidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoropiperidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3,3-difluoropiperidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 349.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.50-11.37 (m, 2H), 8.07 (d, J=1.2 Hz, 1H), 7.95 (d, J=6.0Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.96 (s, 1H), 4.68 (t, J=12.0 Hz, 2H),3.80 (t, J=5.3 Hz, 2H), 2.14 (tt, J=14.4, 6.6 Hz, 2H), 1.91-1.79 (m,2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.42 (s, 3F), −100.53 (p, J=13.2 Hz,2F).

Example 94.5-(8-(3-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-azabicyclo[3.2.1]octan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewithbicyclo[3.2.1]octan-3-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 339.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.44-11.34 (m, 2H), 8.04 (d, J=1.2 Hz, 1H), 7.93 (d, J=6.1Hz, 1H), 7.58 (t, J=1.4 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 4.57 (d, J=11.7Hz, 2H), 3.07 (dd, J=12.0, 1.5 Hz, 2H), 2.37 (d, J=5.0 Hz, 2H),1.73-1.53 (m, 6H).

Example 95.5-(8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture of TFA salts in the manner describedfor Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 432.07 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.60-11.51 (m, 2H), 8.36 (d, J=1.4 Hz, 1H),8.04 (d, J=6.1 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.70-7.62 (m, 2H), 7.61(s, 1H), 7.47 (dd, J=10.7, 8.5 Hz, 1H), 2.93 (ddd, J=9.1, 6.3, 4.4 Hz,1H), 2.78 (ddd, J=9.0, 6.0, 4.4 Hz, 1H), 2.08 (q, J=5.0, 4.4 Hz, 1H),1.86 (ddd, J=8.8, 6.4, 5.1 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −60.42(d, J=12.5 Hz, 3F), −75.14, −120.29 (dtq, J=17.1, 11.6, 6.0, 5.4 Hz,1F).

Example 96.5-(8-cyclopropyl-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-cyclopropyl-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(2-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 414.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.50 (s, 2H), 8.37 (s, 1H), 8.02 (s, 1H), 7.89 (t, J=7.8 Hz,2H), 7.78 (t, J=7.6 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.41 (s, 1H), 2.44(td, J=8.6, 4.4 Hz, 1H), 1.39 (dt, J=6.1, 3.2 Hz, 2H), 1.21 (dt, J=8.4,3.3 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −57.14 (s, 3F).

Example 97.5-(8-cyclopropyl-2-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-cyclopropyl-2-(pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as an HCl salt in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-4-yl)imidazo[1,2-b]pyridazine.Isolation was accomplished via filtration. ES/MS m/z: 347.10 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.59 (d, J=6.3 Hz, 1H), 11.54 (d, J=1.9 Hz,1H), 9.31 (d, J=1.2 Hz, 1H), 8.90 (d, J=6.6 Hz, 2H), 8.48 (d, J=6.7 Hz,2H), 8.04 (d, J=6.2 Hz, 1H), 7.45 (s, 1H), 2.56 (ddd, J=8.4, 6.3, 4.1Hz, 1H), 1.38-1.21 (m, 4H).

Example 98.5-(8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture of TFA salts in the manner describedfor Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic8-((1S,2S)-2-(4-chloro-3-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 398.10 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.59-11.51 (m, 2H), 8.34 (d, J=1.5 Hz, 1H),8.03 (d, J=6.1 Hz, 1H), 7.89 (s, 1H), 7.59 (s, 1H), 7.51 (t, J=8.2 Hz,1H), 7.35 (dd, J=10.9, 2.1 Hz, 1H), 7.16 (dd, J=8.4, 2.0 Hz, 1H), 2.84(ddd, J=9.0, 6.2, 4.4 Hz, 1H), 2.76 (ddd, J=8.8, 6.0, 4.3 Hz, 1H), 2.09(dt, J=8.8, 5.3 Hz, 1H), 1.81 (ddd, J=8.7, 6.3, 5.0 Hz, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.15 (s, 3F), −117.14 (dd, J=10.8, 8.0 Hz, 1F).

Example 99.5-(8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(3-chloro-4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture of TFA salts in the manner describedfor Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic8-((1S,2S)-2-(3-chloro-4-fluorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 398.08 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.60 (dd, J=6.3, 1.9 Hz, 1H), 11.56 (d, J=1.9Hz, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.05 (d, J=6.2 Hz, 1H), 7.96 (d, J=1.6Hz, 1H), 7.63 (s, 1H), 7.50 (dd, J=7.1, 2.2 Hz, 1H), 7.35 (t, J=8.9 Hz,1H), 7.29 (ddd, J=8.6, 4.8, 2.2 Hz, 1H), 2.78 (dddd, J=19.0, 8.8, 6.1,4.4 Hz, 2H), 2.02 (dt, J=8.8, 5.4 Hz, 1H), 1.82 (ddd, J=8.7, 6.4, 5.0Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.19 (s, 3F), −120.53 (ddd,J=9.0, 7.0, 4.7 Hz, 1F).

Example 100.5-(8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture of TFA salts in the manner describedfor Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 432.10 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.53 (s, 2H), 8.30 (s, 1H), 8.01 (d, J=6.3 Hz,1H), 7.81 (s, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.44 (d, J=12.4Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 2.97 (dt, J=9.6, 5.5 Hz, 1H), 2.84 (dt,J=9.7, 5.6 Hz, 1H), 2.21 (dt, J=9.0, 5.5 Hz, 1H), 1.86 (dt, J=8.7, 5.4Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −60.12 (d, J=12.0 Hz, 3F), −74.93,−116.77 (pd, J=12.0, 7.6 Hz, 1F).

Example 101.5-(8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture of TFA salts in the manner describedfor Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-methoxyphenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 376.20 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.61-11.47 (m, 2H), 8.37 (s, 1H), 8.04 (d,J=6.0 Hz, 1H), 7.93 (s, 1H), 7.61 (s, 1H), 7.22 (ddd, J=8.5, 7.4, 1.7Hz, 1H), 7.11 (dd, J=7.7, 1.7 Hz, 1H), 7.01-6.88 (m, 2H), 3.74 (s, 3H),2.91 (td, J=9.2, 5.6 Hz, 1H), 2.65 (dt, J=8.8, 5.3 Hz, 1H), 1.96 (dt,J=9.8, 5.1 Hz, 1H), 1.74 (ddd, J=8.6, 6.6, 4.7 Hz, 1H).

Example 102.5-(8-cyclopropyl-2-(pyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-cyclopropyl-2-(pyridin-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a TFA salt in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-3-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 347.11 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.49 (d, J=7.0 Hz, 2H), 9.27 (d, J=2.1 Hz, 1H), 8.91 (s,1H), 8.59 (d, J=4.7 Hz, 1H), 8.47 (d, J=8.0 Hz, 1H), 8.00 (d, J=6.0 Hz,1H), 7.59 (dd, J=7.6, 5.2 Hz, 1H), 7.35 (s, 1H), 2.60-2.53 (m, 1H),1.35-1.20 (m, 4H).

Example 103.5-(8-cyclopropyl-2-(pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-cyclopropyl-2-(pyridin-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a TFA salt in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-(pyridin-2-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 347.14 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.63-11.38 (m, 2H), 8.66 (s, 1H), 8.64 (ddd, J=4.9, 1.6, 0.9Hz, 1H), 8.19 (d, J=7.8 Hz, 1H), 8.01 (d, J=6.4 Hz, 1H), 7.95 (td,J=7.9, 1.6 Hz, 1H), 7.40 (ddd, J=7.5, 5.1, 1.2 Hz, 1H), 7.36 (s, 1H),2.57-2.54 (m, 1H), 1.35-1.20 (m, 4H).

Example 104.5-(8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dioneand5-(8-((1R,2R)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dione

5-(8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 346.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.38 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.07(d, J=1.9 Hz, 1H), 8.01 (s, 1H), 7.38-7.22 (m, 5H), 2.74 (t, J=7.5 Hz,2H), 1.93 (tt, J=7.5, 3.7 Hz, 2H).

5-(8-((1S,2S)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dioneand5-(8-((1R,2R)-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4-(1H,3H)-dionewere chirally separated by SFC AD-H column (35% MeOH).

Example 105.5-(8-((1S,2R)-2-benzylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2S)-2-benzylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2R)-2-benzylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2R)-2-benzylcyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 360.20 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.34 (d, J=2.0 Hz, 1H), 8.24 (s, 1H), 8.08(d, J=1.6 Hz, 1H), 7.82 (s, 1H), 7.34-7.14 (m, 5H), 3.02-2.78 (m, 2H),2.42-2.32 (m, 1H), 1.93-1.85 (m, 1H), 1.50-1.38 (m, 2H).

Example 106.5-(8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2S)-2-(3,3-difluorocyclobutyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2R)-2-(3,3-difluorocyclobutyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z 360.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.36 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.09(d, J=2.0 Hz, 1H), 7.86 (s, 1H), 2.85-2.66 (m, 2H), 2.51-2.35 (m, 2H),2.36-2.28 (m, 1H), 2.26-2.11 (m, 1H), 1.86-1.75 (m, 1H), 1.48-1.33 (m,2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.71 (s, 3F), −84.96-−85.76 (m,1F), −98.02-−98.82 (m, 1F).

Example 107.5-(8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished by RP-HPLC (5-100%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z 338.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 8.10 (s, 1H), 7.69 (s, 1H),7.59 (s, 1H), 2.96-2.85 (m, 1H), 2.72-2.62 (m, 1H), 1.72-1.57 (m, 2H).¹⁹F NMR (376 MHz, Methanol-d4) δ −69.25 (d, J=6.6 Hz, 3F), −77.49 (s,3F).

Example 108.5-(8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1S,2S)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1R,2R)-2-fluoro-2-phenylcyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 364.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.35 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.22(s, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.50-7.35 (m, 5H), 3.10-2.99 (m, 1H),2.36 (dt, J=20.8, 8.0 Hz, 1H), 2.29-2.19 (m, 1H). ¹⁹F NMR (377 MHz,Methanol-d4) δ −77.80 (s, 3F), −188.55 (m, 1F).

Example 109.5-(8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 371.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.44 (s, 1H), 8.12 (d, J=1.2 Hz, 1H), 7.95 (td, J=3.1, 1.1Hz, 1H), 7.62 (d, J=1.2 Hz, 1H), 6.69 (s, 1H), 4.65 (t, J=13.1 Hz, 4H).¹⁹F NMR (376 MHz, DMSO-d6) δ −74.15 (s, 3F), −122.65 (td, J=13.9, 12.3,5.2 Hz, 4F).

Example 110.5-(8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-41R,2R)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 426.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.39 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 8.09(d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.21-7.09 (m, 3H), 2.84-2.67 (m, 2H),1.93 (ddd, J=8.1, 6.6, 1.4 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −52.99(d, J=4.1 Hz, 2F), −77.78 (s, 3F)

Example 111.4-(41R,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrileand4-(((1S,2R)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrile

4-(((1R,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrilewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-(((1R,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)methyl)benzonitrile(racemic mixture). Purification was accomplished via RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 385.10 [M+H]. ¹HNMR (400 MHz, Acetonitrile-d3) δ 8.15 (d, J=1.9 Hz, 1H), 8.08 (d, J=6.5Hz, 1H), 7.97 (d, J=1.9 Hz, 1H), 7.76 (s, 1H), 7.72-7.61 (m, 2H),7.57-7.42 (m, 2H), 3.08-2.88 (m, 3H), 1.86-1.75 (m, 1H), 1.54-1.37 (m,2H).

Example 115.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile(Racemic Mixture)

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-fluoro-benzonitrile.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 389.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.54 (d, J=3.7 Hz, 2H), 8.31 (d, J=1.4 Hz, 1H), 8.02 (d,J=6.4 Hz, 1H), 7.88-7.79 (m, 2H), 7.58 (s, 1H), 7.47 (dd, J=11.1, 1.5Hz, 1H), 7.34 (dd, J=8.2, 1.6 Hz, 1H), 2.96 (dd, J=8.8, 5.1 Hz, 1H),2.86 (ddd, J=8.9, 6.2, 4.4 Hz, 1H), 2.24 (dt, J=8.7, 5.4 Hz, 1H), 1.89(dt, J=8.8, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.04, −109.50(dd, J=11.0, 7.2 Hz).

Example 117.5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 486.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 2H), 8.31(s, 1H), 8.03 (d, J=6.3 Hz, 1H), 7.85-7.80 (m, 1H), 7.78-7.67 (m, 2H),7.58 (s, 1H), 7.24-7.17 (m, 1H), 5.31 (q, J=9.0 Hz, 2H), 3.03 (dt,J=9.6, 5.7 Hz, 1H), 2.83 (dt, J=9.6, 5.3 Hz, 1H), 2.18 (dt, J=10.0, 5.3Hz, 1H), 1.91 (q, J=6.3 Hz, 1H).

Example 118.5-(8-((1S,2S)-2-(1-((2,2-difluorocyclopropyl)methyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-((2,2-difluorocyclopropyl)methyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[1-[(2,2-difluorocyclopropyl)methyl]indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 476.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (d, J=8.3 Hz,2H), 8.38 (d, J=4.5 Hz, 1H), 8.06 (q, J=3.5, 2.7 Hz, 2H), 7.94 (d, J=7.9Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.63 (d, J=3.5 Hz, 2H), 7.06 (d, J=8.4Hz, 1H), 4.62-4.45 (m, 2H), 3.02-2.92 (m, 1H), 2.88-2.79 (m, 1H), 2.29(ddq, J=14.8, 12.0, 7.3 Hz, 1H), 2.11 (dt, J=11.0, 5.6 Hz, 1H),1.99-1.91 (m, 1H), 1.66 (dq, J=11.4, 5.3 Hz, 1H), 1.55-1.42 (m, 1H).

Example 119.5-(8-((1S,2S)-2-(1-isopropyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(1-isopropyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-isopropyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(1-isopropyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(1-isopropylindazol-6-yl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic). ES/MS m/z: 428.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.58-11.52 (m, 2H), 8.36-8.31 (m, 1H), 8.07-7.98 (m, 2H), 7.86 (s, 1H),7.68 (d, J=8.4 Hz, 1H), 7.62-7.56 (m, 2H), 7.02 (dd, J=8.5, 1.4 Hz, 1H),5.00 (p, J=6.6 Hz, 1H), 2.97 (ddd, J=9.0, 6.2, 4.2 Hz, 1H), 2.87-2.77(m, 1H), 2.16-2.06 (m, 1H), 1.93 (dt, J=8.8, 5.6 Hz, 1H), 1.47 (dd,J=9.3, 6.6 Hz, 6H).

Example 120.5-(8-((1S,2S)-2-(1-isopropyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-[8-[(1S,2S)-2-(1-isopropylindazol-6-yl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas chirally separated from the Example 119 by SFC AD-H column (35%EtOH). ES/MS m/z: 428.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s,2H), 8.33 (d, J=1.4 Hz, 1H), 8.07-7.98 (m, 2H), 7.85 (s, 1H), 7.68 (d,J=8.3 Hz, 1H), 7.59 (d, J=4.8 Hz, 2H), 7.02 (dd, J=8.4, 1.3 Hz, 1H),5.00 (p, J=6.6 Hz, 1H), 3.03-2.93 (m, 1H), 2.86-2.77 (m, 1H), 2.11 (dq,J=9.5, 4.8 Hz, 1H), 1.93 (dt, J=8.6, 5.5 Hz, 1H), 1.47 (dd, J=9.3, 6.6Hz, 6H).

Example 121.5-(8-((1S,2S)-2-(6-(difluoromethoxy)pyridin-3-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(6-(difluoromethoxy)pyridin-3-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(6-(difluoromethoxy)pyridin-3-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(6-(difluoromethoxy)pyridin-3-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine(racemic). ES/MS m/z: 431.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54(d, J=4.0 Hz, 2H), 8.24 (d, J=2.5 Hz, 1H), 8.03 (d, J=6.4 Hz, 1H),7.86-7.50 (m, 1H), 7.80 (dd, J=8.5, 2.5 Hz, 1H), 7.55 (d, J=7.1 Hz, 1H),7.52-7.50 (m, 1H), 7.06 (d, J=8.5 Hz, 1H), 2.92-2.87 (m, 1H), 2.79-2.66(m, 1H), 2.14 (dt, J=9.1, 5.4 Hz, 1H), 1.79 (ddd, J=8.8, 6.3, 4.8 Hz,1H).

Example 122.5-(8-((1S,2S)-2-(6-(difluoromethoxy)pyridin-3-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-[8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas chirally separated from the Example 121 by SFC OJ-H column (25%EtOH). ES/MS m/z: 431.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d,J=4.7 Hz, 2H), 8.24 (d, J=2.4 Hz, 1H), 8.03 (d, J=6.3 Hz, 1H), 7.86-7.49(m, 1H), 7.80 (dd, J=8.6, 2.6 Hz, 1H), 7.56 (d, J=7.1 Hz, 1H), 7.51 (s,1H), 7.06 (d, J=8.5 Hz, 1H), 2.91 (ddd, J=9.0, 6.3, 4.4 Hz, 1H), 2.71(ddd, J=8.9, 5.9, 4.5 Hz, 1H), 2.14 (dt, J=8.9, 5.3 Hz, 1H), 1.84-1.74(m, 1H).

Example 123.5-(8-((1S,2S)-2-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 450.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 2H), 8.34(s, 1H), 8.14-7.99 (m, 2H), 7.86 (s, 1H), 7.77-7.54 (m, 3H), 7.09 (d,J=8.4 Hz, 1H), 6.43 (t, J=54.9 Hz, 1H), 4.91 (t, J=14.9 Hz, 2H), 3.00(s, 1H), 2.82 (d, J=7.9 Hz, 1H), 2.13 (d, J=8.2 Hz, 1H), 1.93 (s, 1H).

Example 124.5-(8-((1R,2R)-2-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-[8-[(1R,2R)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas chirally separated from the Example 123 by SFC AD-H column (35%EtOH). ES/MS m/z: 450.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (d,J=4.7 Hz, 2H), 8.31 (d, J=1.3 Hz, 1H), 8.10 (d, J=0.9 Hz, 1H), 8.06-7.99(m, 1H), 7.82 (s, 1H), 7.75-7.64 (m, 2H), 7.56 (s, 1H), 7.08 (dd, J=8.4,1.3 Hz, 1H), 6.57-6.29 (t, J=3.9 Hz, 1H), 4.91 (td, J=15.0, 3.8 Hz, 2H),3.05-2.96 (m, 1H), 2.81 (dt, J=8.9, 5.4 Hz, 1H), 2.19-2.06 (m, 1H), 1.91(dt, J=8.5, 5.3 Hz, 1H)

Example 125.5-(8-((1S,2S)-2-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2-difluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas chirally separated from the Example 123 by SFC AD-H column (35%EtOH). ES/MS m/z: 450.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (s,2H), 8.30 (s, 1H), 8.10 (s, 1H), 8.02 (d, J=6.2 Hz, 1H), 7.85-7.65 (m,3H), 7.55 (s, 1H), 7.08 (dd, J=8.4, 1.3 Hz, 1H), 6.43 (tt, J=54.9, 3.7Hz, 1H), 4.91 (td, J=15.1, 3.8 Hz, 2H), 3.05-2.93 (m, 1H), 2.86-2.77 (m,1H), 2.20-2.10 (m, 1H), 1.96-1.83 (m, 1H).

Example 126.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[2,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 468.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 2H), 8.33(d, J=1.5 Hz, 1H), 8.07-8.00 (m, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.86 (s,1H), 7.59 (s, 1H), 7.53 (d, J=3.7 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.57(d, J=3.6 Hz, 1H), 5.18 (h, J=8.3 Hz, 2H), 3.04 (dddd, J=28.6, 9.7, 6.0,4.1 Hz, 2H), 2.13-1.98 (m, 2H).

Example 127.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 468.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.59-11.51 (m,2H), 9.21 (s, 1H), 8.31 (d, J=1.3 Hz, 1H), 8.24 (s, 1H), 8.04 (d, J=6.1Hz, 1H), 7.93 (d, J=3.5 Hz, 1H), 7.78 (d, J=1.3 Hz, 1H), 7.65 (s, 1H),7.10 (d, J=3.5 Hz, 1H), 5.46 (q, J=9.0 Hz, 2H), 3.53 (dd, J=9.2, 5.0 Hz,1H), 3.05-2.95 (m, 1H), 2.43 (dd, J=9.4, 5.6 Hz, 1H), 2.11 (dt, J=9.5,5.5 Hz, 1H).

Example 128.5-(8-((1S,2S)-2-(3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-cyclopropyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[3-cyclopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 508.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 2H), 8.32(s, 1H), 8.06-7.99 (m, 1H), 7.83 (s, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.63(s, 1H), 7.56 (s, 1H), 7.07 (dd, J=8.4, 1.4 Hz, 1H), 5.27 (q, J=9.1 Hz,2H), 2.99 (dt, J=9.2, 5.5 Hz, 1H), 2.79 (dt, J=9.6, 5.4 Hz, 1H),2.34-2.23 (m, 1H), 2.18-2.06 (m, 1H), 1.90 (dd, J=8.8, 5.3 Hz, 1H),1.07-0.91 (m, 4H).

Example 129.5-(8-((1S,2S)-2-(1-(2,2-difluoroethyl)-7-fluoro-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2-difluoroethyl)-7-fluoro-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(1-(2,2-difluoroethyl)-7-fluoro-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 468.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J=6.0 Hz,2H), 8.38 (d, J=1.5 Hz, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.04 (d, J=6.0 Hz,1H), 7.92 (s, 1H), 7.69-7.56 (m, 2H), 7.02 (dd, J=8.5, 6.0 Hz, 1H), 6.44(tt, J=54.7, 3.6 Hz, 1H), 4.91 (td, J=15.0, 3.6 Hz, 2H), 3.16 (dt,J=8.7, 5.4 Hz, 1H), 2.85 (dt, J=8.9, 5.4 Hz, 1H), 2.15 (dt, J=8.9, 5.3Hz, 1H), 1.98-1.85 (m, 1H).

Example 130.5-(8-((1S,2S)-2-(1-(cyclopropylmethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(cyclopropylmethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[1-(cyclopropylmethyl)indazol-6-yl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 440.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J=5.5 Hz,2H), 8.36 (d, J=1.4 Hz, 1H), 8.08-7.97 (m, 2H), 7.90 (s, 1H), 7.69 (d,J=8.4 Hz, 1H), 7.61 (s, 2H), 7.02 (dd, J=8.4, 1.3 Hz, 1H), 4.28 (d,J=6.9 Hz, 2H), 2.97 (ddd, J=9.4, 6.3, 4.4 Hz, 1H), 2.87-2.77 (m, 1H),2.10 (dt, J=8.9, 5.3 Hz, 1H), 1.99-1.89 (m, 1H), 1.28 (tq, J=7.4, 4.8Hz, 1H), 0.54-0.42 (m, 2H), 0.46-0.34 (m, 2H).

Example 131.5-(8-((1S,2S)-2-(2-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(trifluoromethyl)quinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J=6.1 Hz,2H), 8.63 (d, J=8.6 Hz, 1H), 8.36 (d, J=1.5 Hz, 1H), 8.14 (d, J=8.8 Hz,1H), 8.09-8.02 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.92-7.81 (m, 2H), 7.66(s, 1H), 3.09 (ddd, J=9.0, 6.2, 4.4 Hz, 1H), 2.94 (ddd, J=8.9, 6.0, 4.4Hz, 1H), 2.22 (dt, J=8.8, 5.4 Hz, 1H), 1.99 (dt, J=8.7, 5.4 Hz, 1H).

Example 132.5-(8-((1S,2S)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 431.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65-11.46 (m,2H), 8.44 (d, J=2.8 Hz, 1H), 8.04 (d, J=6.2 Hz, 1H), 7.65-7.49 (m, 4H),7.28 (t, J=73.6 Hz, 1H), 3.06 (ddd, J=8.7, 5.9, 4.2 Hz, 1H), 2.93 (ddd,J=8.9, 6.0, 4.1 Hz, 1H), 2.08 (ddd, J=8.4, 6.0, 4.0 Hz, 1H), 1.91-1.84(m, 1H).

Example 133.5-(8-((1S,2S)-2-(3-(trifluoromethyl)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(trifluoromethyl)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-(trifluoromethyl)isoquinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63 (dd, J=23.1,4.1 Hz, 2H), 9.45 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 8.27 (d, J=8.6Hz, 1H), 8.14-8.04 (m, 3H), 7.84-7.75 (m, 2H), 3.05 (t, J=7.4 Hz, 2H),2.24-2.14 (m, 1H), 2.03 (td, J=7.7, 5.1 Hz, 1H).

Example 134.5-(3-fluoro-8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 483.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.60-11.53 (m,2H), 9.00 (dd, J=4.4, 1.5 Hz, 1H), 8.44 (dd, J=8.4, 1.7 Hz, 1H), 8.19(d, J=1.9 Hz, 1H), 8.11 (d, J=1.9 Hz, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.68(dd, J=8.4, 4.2 Hz, 1H), 7.58 (d, J=7.4 Hz, 2H), 3.25-3.15 (m, 1H), 2.91(dt, J=10.0, 5.4 Hz, 1H), 2.24 (dt, J=9.0, 5.4 Hz, 1H), 1.99 (dt, J=8.8,5.5 Hz, 1H).

Example 135.5-(8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (d, J=7.1 Hz,2H), 9.04-8.98 (m, 1H), 8.45 (dd, J=8.5, 1.6 Hz, 1H), 8.38 (s, 1H), 8.19(s, 1H), 8.13-8.02 (m, 2H), 7.91 (s, 1H), 7.73-7.65 (m, 2H), 3.15 (dt,J=10.0, 5.7 Hz, 1H), 2.93 (dt, J=10.0, 5.2 Hz, 1H), 2.20 (dt, J=10.4,5.6 Hz, 1H), 2.03 (dt, J=11.1, 5.7 Hz, 1H).

Example 136.5-(8-((1S,2S)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic). ES/MS m/z: 413.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.85-11.61 (m, 2H), 8.59 (d, J=1.9 Hz, 1H), 8.46 (d, J=2.8 Hz, 1H),8.23 (d, J=1.9 Hz, 1H), 8.12 (d, J=6.3 Hz, 1H), 7.86 (s, 1H), 7.69-7.54(m, 2H), 7.30 (t, J=73.5 Hz, 1H), 3.12-2.92 (m, 2H), 1.94 (m, 2H).

Example 137.5-(8-((1S,2S)-2-(5-(difluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-[8-[(1S,2S)-2-[5-(difluoromethoxy)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas chirally separated from the Example 136 by SFC AD-H column (35%MeOH-DEA). ES/MS m/z: 413.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.63-11.54 (m, 2H), 8.42 (dd, J=17.0, 2.1 Hz, 2H), 8.06 (d, J=6.2 Hz,1H), 7.95 (s, 1H), 7.70-7.50 (m, 3H), 7.28 (t, J=73.6 Hz, 1H), 3.05-2.92(m, 2H), 2.02-1.89 (m, 2H).

Example 138.5-(8-((1S,2S)-2-(3-(trifluoromethyl)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(3-(trifluoromethyl)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(trifluoromethyl)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(3-(trifluoromethyl)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-(trifluoromethyl)isoquinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62 (dd, J=20.3,4.1 Hz, 2H), 9.45 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 8.27 (d, J=8.6Hz, 1H), 8.13-8.02 (m, 3H), 7.84-7.72 (m, 2H), 3.05 (ddd, J=9.0, 6.6,2.4 Hz, 2H), 2.24-2.14 (m, 1H), 2.03 (td, J=8.3, 7.8, 5.1 Hz, 1H).

Example 139.5-(8-((1S,2S)-2-(4-(trifluoromethyl)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(trifluoromethyl)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-4-(trifluoromethyl)quinoline.ES/MS m/z: 465.10 [M+1-1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65-11.56 (m,2H), 9.06 (dd, J=4.3, 1.5 Hz, 1H), 8.51-8.40 (m, 2H), 8.21 (s, 1H), 8.08(d, J=6.2 Hz, 1H), 8.05-7.97 (m, 2H), 7.76-7.67 (m, 2H), 3.15 (ddd,J=9.0, 6.3, 4.4 Hz, 1H), 3.05-2.95 (m, 1H), 2.20 (dt, J=9.0, 5.5 Hz,1H), 2.10 (dt, J=8.6, 5.6 Hz, 1H).

Example 140.5-(8-((1S,2S)-2-(6-(difluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(6-(difluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[6-(difluoromethoxy)-3-pyridyl]cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 413.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62 (m, 2H), 8.46(s, 1H), 8.25 (d, J=2.5 Hz, 1H), 8.08-8.07 (m, 2H), 7.87-7.51 (m, 1H),7.81 (dd, J=8.6, 2.6 Hz, 1H), 7.71 (s, 1H), 7.08 (d, J=8.5 Hz, 1H), 2.83(dt, J=8.6, 5.5 Hz, 2H), 2.04 (dt, J=8.9, 5.4 Hz, 1H), 1.92-1.82 (m,1H).

Example 141.5-(8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(8-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (d, J=6.8 Hz,2H), 9.01 (dd, J=4.2, 1.8 Hz, 1H), 8.45 (dd, J=8.5, 1.8 Hz, 1H), 8.38(d, J=1.5 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.14-8.03 (m, 2H), 7.92 (s,1H), 7.73-7.65 (m, 2H), 3.14 (ddd, J=8.9, 6.2, 4.4 Hz, 1H), 2.93 (ddd,J=8.8, 6.0, 4.4 Hz, 1H), 2.19 (dt, J=8.9, 5.5 Hz, 1H), 2.04 (dt, J=8.7,5.5 Hz, 1H).

Example 142.5-(8-((1S,2S)-2-(2-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(2-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(2-(trifluoromethyl)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-2-(trifluoromethyl)quinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 2H), 8.63(d, J=8.6 Hz, 1H), 8.36 (d, J=1.4 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H),8.08-8.02 (m, 2H), 7.97 (d, J=8.6 Hz, 1H), 7.91-7.81 (m, 2H), 7.65 (s,1H), 3.09 (ddd, J=9.0, 6.2, 4.4 Hz, 1H), 2.94 (ddd, J=8.8, 5.9, 4.3 Hz,1H), 2.22 (dt, J=8.8, 5.3 Hz, 1H), 1.99 (dt, J=8.6, 5.3 Hz, 1H).

Example 143.5-(8-((1S,2S)-2-(benzo[d]thiazol-6-yl)cyclopropyl)-2-cyclopropylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(benzo[d]thiazol-6-yl)cyclopropyl)-2-cyclopropylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[2-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1,3-benzothiazole(racemic).ES/MS m/z: 443.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 9.24 (s, 1H),8.28 (s, 1H), 8.15 (s, 1H), 8.10-8.01 (m, 3H), 7.51 (dd, J=8.5, 1.9 Hz,1H), 2.96-2.86 (m, 1H), 2.82 (dt, J=9.9, 5.1 Hz, 1H), 2.23-2.11 (m, 1H),2.11-1.93 (m, 2H), 1.26-1.16 (m, 2H), 1.02 (dt, J=6.6, 4.4 Hz, 2H).

Example 144.5-(3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 433.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=4.3 Hz,2H), 8.90 (dd, J=2.3, 1.2 Hz, 1H), 8.14-7.98 (m, 2H), 7.70 (d, J=8.2 Hz,1H), 7.58-7.43 (m, 2H), 3.18 (ddd, J=8.7, 5.8, 4.1 Hz, 1H), 3.03 (ddd,J=8.9, 6.2, 4.1 Hz, 1H), 2.19 (ddd, J=8.6, 6.2, 4.0 Hz, 1H), 1.93 (ddd,J=9.3, 3.9 Hz, 1H).

Example 145.5-(2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-cyclopropyl-8-(3,3-difluoro-4,4-dimethyl-pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 403.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41-11.30 (m,2H), 7.89 (d, J=6.2 Hz, 1H), 7.81 (s, 1H), 6.53 (s, 1H), 4.40 (s, 2H),3.78 (s, 2H), 2.00 (tt, J=8.3, 5.0 Hz, 1H), 1.21 (s, 6H), 0.96-0.85 (m,2H), 0.88-0.77 (m, 2H).

Example 146.5-(2-cyclopropyl-8-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(2-cyclopropyl-8-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-cyclopropyl-8-[(1S,2S)-2-(2,4-difluorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 422.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.67-11.61 (m,1H), 11.57 (d, J=2.0 Hz, 1H), 8.28 (s, 1H), 8.03 (d, J=6.2 Hz, 1H), 7.69(s, 1H), 7.39 (td, J=8.8, 6.4 Hz, 1H), 7.25 (ddd, J=10.7, 9.3, 2.6 Hz,1H), 7.16-7.06 (m, 1H), 2.83-2.75 (m, 2H), 2.21-2.06 (m, 1H), 1.88 (dt,J=15.4, 6.2 Hz, 2H), 1.09 (dq, J=6.2, 3.8 Hz, 2H), 0.96 (dq, J=7.1, 4.5,4.1 Hz, 2H).

Example 147.5-(7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(2,4-dimethoxypyrimidin-5-yl)-7-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 343.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.68 (d, J=63.9Hz, 2H), 8.43 (d, J=6.1 Hz, 1H), 8.09 (d, J=2.3 Hz, 1H), 6.92 (s, 1H),6.43 (s, 1H), 4.59-4.21 (m, 2H), 3.93-3.70 (m, 3H), 1.20-0.81 (m, 4H).

Example 148.5-(3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 361.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54-11.29 (m,2H), 7.97 (d, J=6.1 Hz, 1H), 7.38 (d, J=7.3 Hz, 1H), 6.56 (s, 1H),3.88-3.86 (m, 5H), 1.16-0.66 (m, 4H).

Example 149.5-(8-((1S,2S)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[5-(trifluoromethyl)-2-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 415.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d, J=4.8 Hz,2H), 8.91 (s, 1H), 8.34 (s, 1H), 8.12 (d, J=8.4 Hz, 1H), 8.04 (d, J=6.1Hz, 1H), 7.86 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.62 (s, 1H), 3.15 (dt,J=9.3, 5.0 Hz, 1H), 3.05 (dt, J=9.7, 5.2 Hz, 1H), 2.15 (dt, J=9.6, 4.9Hz, 1H), 1.96 (dt, J=9.4, 4.8 Hz, 1H).

Example 150.5-(8-((1S,2S)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas chirally separated from the Example 149 by SFC AD-H column (20%EtOH). ES/MS m/z: 415.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (d,J=4.7 Hz, 2H), 8.97-8.84 (m, 1H), 8.31 (d, J=1.4 Hz, 1H), 8.11 (dd,J=8.4, 2.4 Hz, 1H), 8.02 (d, J=6.3 Hz, 1H), 7.81 (s, 1H), 7.71 (d, J=8.2Hz, 1H), 7.58 (s, 1H), 3.20-3.02 (m, 2H), 2.18 (ddd, J=9.0, 6.1, 3.9 Hz,1H), 1.95 (ddd, J=9.2, 5.7, 4.0 Hz, 1H).

Example 151.6-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrile

6-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrilewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]pyridine-3-carbonitrile(racemic).ES/MS m/z: 390.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57-11.51 (m,2H), 8.96 (d, J=2.2 Hz, 1H), 8.20 (dd, J=8.2, 2.2 Hz, 1H), 8.03 (d,J=6.4 Hz, 1H), 7.69 (dd, J=8.3, 0.9 Hz, 1H), 7.59-7.50 (m, 2H), 3.16(ddd, J=8.6, 5.7, 4.1 Hz, 1H), 3.02 (ddd, J=9.1, 6.3, 4.1 Hz, 1H), 2.23(ddd, J=8.6, 6.3, 4.0 Hz, 1H), 1.93 (ddd, J=9.3, 5.7, 4.0 Hz, 1H).

Example 152.5-(8-((1S,2S)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[6-(trifluoromethyl)-3-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 415.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ) δ 11.59-11.56 (m,2H), 8.74 (d, J=2.1 Hz, 1H), 8.37 (d, J=1.5 Hz, 1H), 8.05 (d, J=6.1 Hz,1H), 7.98-7.88 (m, 2H), 7.86 (d, J=8.2 Hz, 1H), 7.66 (s, 1H), 2.99 (ddd,J=9.0, 6.2, 4.4 Hz, 1H), 2.89 (ddd, J=8.8, 6.1, 4.5 Hz, 1H), 2.22 (dt,J=8.9, 5.4 Hz, 1H), 1.99-1.89 (m, 1H).

Example 153.5-(8-((1S,2S)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(6-(trifluoromethyl)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas chirally separated from the Example 152 by SFC OD-H column (20%IPA-NH₃). ES/MS m/z: 415.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d,J=4.7 Hz, 2H), 8.75 (d, J=2.1 Hz, 1H), 8.34 (d, J=1.4 Hz, 1H), 8.04 (d,J=6.3 Hz, 1H), 7.94 (dd, J=8.2, 2.2 Hz, 1H), 7.89-7.82 (m, 2H), 7.63 (s,1H), 3.01 (ddd, J=9.3, 6.2, 4.4 Hz, 1H), 2.89 (ddd, J=8.9, 6.1, 4.3 Hz,1H), 2.24 (dt, J=8.9, 5.3 Hz, 1H), 1.93 (dt, J=8.7, 5.3 Hz, 1H).

Example 154.5-(8-((1S,2S)-2-(quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic).ES/MS m/z: 397.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.71 (d, J=6.2 Hz,1H), 11.61 (d, J=2.0 Hz, 1H), 9.18 (dd, J=5.1, 1.6 Hz, 1H), 8.97 (d,J=8.3 Hz, 1H), 8.50 (d, J=1.7 Hz, 1H), 8.27 (d, J=8.6 Hz, 1H), 8.18-8.07(m, 3H), 7.91 (dd, J=8.3, 5.1 Hz, 1H), 7.83-7.75 (m, 2H), 3.20-3.08 (m,2H), 2.25-2.15 (m, 1H), 2.05 (dt, J=8.5, 5.5 Hz, 1H).

Example 155.6-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrile

6-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrilewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]pyridine-3-carbonitrile(racemic).ES/MS m/z: 372.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.71-11.65 (m,1H), 11.60 (d, J=2.0 Hz, 1H), 8.99 (dd, J=2.3, 0.8 Hz, 1H), 8.49 (d,J=1.7 Hz, 1H), 8.23 (dd, J=8.2, 2.2 Hz, 1H), 8.09 (d, J=6.3 Hz, 2H),7.78 (s, 1H), 7.69 (dd, J=8.2, 0.9 Hz, 1H), 3.10 (ddt, J=8.9, 6.4, 3.4Hz, 2H), 2.05 (dddd, J=31.9, 8.2, 6.4, 4.1 Hz, 2H).

Example 156.5-(8-((1S,2S)-2-(isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]isoquinoline(racemic).ES/MS m/z: 397.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.84-11.76 (m,1H), 11.63 (d, J=2.0 Hz, 1H), 9.21 (dd, J=5.2, 1.5 Hz, 1H), 8.97 (d,J=8.3 Hz, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.38-8.25 (m, 2H), 8.21 (s, 1H),8.13 (d, J=6.2 Hz, 1H), 8.03 (ddd, J=16.3, 8.7, 3.5 Hz, 2H), 7.87 (s,1H), 3.28 (dt, J=9.8, 5.2 Hz, 1H), 3.11-3.01 (m, 1H), 2.12 (dt, J=8.9,5.5 Hz, 1H), 2.04 (dt, J=8.6, 5.6 Hz, 1H).

Example 157.5-(8-((1S,2S)-2-(quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic).ES/MS m/z: 397.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.82 (dd, J=6.4,2.0 Hz, 1H), 11.63 (d, J=2.0 Hz, 1H), 9.86 (s, 1H), 8.66 (d, J=6.6 Hz,1H), 8.58-8.48 (m, 2H), 8.37 (d, J=6.5 Hz, 1H), 8.28 (d, J=1.6 Hz, 1H),8.20-8.09 (m, 2H), 7.96 (dd, J=8.7, 1.7 Hz, 1H), 7.87 (s, 1H), 3.39 (dd,J=8.8, 4.9 Hz, 1H), 3.11 (ddd, J=9.1, 6.3, 4.3 Hz, 1H), 2.21 (dt, J=8.7,5.4 Hz, 1H), 2.11 (dt, J=8.8, 5.5 Hz, 1H).

Example 158.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]benzonitrile.ES/MS m/z: 389.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63 (dd, J=6.2,2.0 Hz, 1H), 11.55 (d, J=2.0 Hz, 1H), 8.04 (d, J=6.2 Hz, 1H), 7.77 (d,J=8.3 Hz, 2H), 7.64 (d, J=6.9 Hz, 1H), 7.55 (s, 1H), 7.51-7.44 (m, 2H),2.93 (ddd, J=9.0, 6.2, 4.4 Hz, 1H), 2.84 (ddd, J=8.9, 6.1, 4.4 Hz, 1H),2.18 (dt, J=8.7, 5.3 Hz, 1H), 1.90-1.80 (m, 1H).

Example 159.5-(8-((1S,2S)-2-(pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 347.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.76 (dd, J=6.3,2.0 Hz, 1H), 11.62 (d, J=2.0 Hz, 1H), 8.67 (dd, J=5.5, 1.6 Hz, 1H), 8.54(d, J=1.7 Hz, 1H), 8.21-8.08 (m, 3H), 7.86 (s, 1H), 7.74 (d, J=8.0 Hz,1H), 7.61 (t, J=6.5 Hz, 1H), 3.27-3.17 (m, 1H), 3.13 (ddd, J=8.7, 6.3,4.3 Hz, 1H), 2.22-2.10 (m, 2H).

Example 160.5-(8-((1S,2S)-2-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-(trifluoromethyl)pyridin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[2-(trifluoromethyl)-4-pyridyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 415.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.74-11.66 (m,1H), 11.61 (d, J=2.0 Hz, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.51 (d, J=1.7 Hz,1H), 8.15-8.06 (m, 2H), 7.86-7.77 (m, 2H), 7.63 (dd, J=5.2, 1.7 Hz, 1H),3.20-3.05 (m, 1H), 2.96 (ddd, J=9.0, 6.2, 4.3 Hz, 1H), 2.15 (dt, J=8.9,5.6 Hz, 1H), 2.03 (dt, J=8.8, 5.6 Hz, 1H).

Example 161.5-(8-((1S,2S)-2-(3-fluoropyridin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-fluoropyridin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-fluoro-4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 365.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.77 (d, J=6.3 Hz,1H), 11.63 (d, J=1.9 Hz, 1H), 8.65 (d, J=2.2 Hz, 1H), 8.59 (d, J=1.8 Hz,1H), 8.50 (d, J=5.2 Hz, 1H), 8.25 (s, 1H), 8.11 (d, J=6.2 Hz, 1H), 7.91(s, 1H), 7.51 (t, J=6.0 Hz, 1H), 3.20 (d, J=10.3 Hz, 1H), 2.97-2.87 (m,1H), 2.13 (dt, J=8.9, 5.5 Hz, 1H), 2.02 (dt, J=8.7, 5.5 Hz, 1H).

Example 162.5-(8-((1S,2S)-2-(pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 347.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=6.8 Hz,2H), 8.78 (d, J=2.1 Hz, 1H), 8.64 (dd, J=5.3, 1.4 Hz, 1H), 8.32 (d,J=1.3 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.83 (d,J=1.3 Hz, 1H), 7.75 (dd, J=8.1, 5.3 Hz, 1H), 7.61 (s, 1H), 3.05 (dt,J=9.5, 5.7 Hz, 1H), 2.88 (ddd, J=8.9, 6.1, 4.5 Hz, 1H), 2.25 (dt, J=8.8,5.3 Hz, 1H), 1.91 (dt, J=8.7, 5.3 Hz, 1H).

Example 163.5-(8-((1S,2S)-2-(quinolin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(quinolin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic).ES/MS m/z: 397.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.64-11.55 (m,2H), 9.06 (d, J=2.1 Hz, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 8.11-7.97 (m,3H), 7.94 (s, 1H), 7.84 (dd, J=8.5, 6.8 Hz, 1H), 7.76-7.68 (m, 2H), 3.13(ddd, J=9.4, 6.1, 4.4 Hz, 1H), 3.01-2.91 (m, 1H), 2.24 (dt, J=8.8, 5.4Hz, 1H), 2.06 (dt, J=8.5, 5.5 Hz, 1H).

Example 164.5-(8-((1S,2S)-2-(5-fluoropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-fluoropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(5-fluoro-3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 365.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.81 (d, J=6.2 Hz,1H), 11.64 (d, J=1.8 Hz, 1H), 8.62 (d, J=1.8 Hz, 1H), 8.51 (d, J=2.4 Hz,2H), 8.31 (s, 1H), 8.14 (d, J=6.2 Hz, 1H), 7.88 (s, 1H), 7.74 (dt,J=10.4, 2.1 Hz, 1H), 3.16 (dt, J=9.7, 5.4 Hz, 1H), 2.88-2.78 (m, 1H),2.00 (dq, J=11.7, 5.3 Hz, 2H).

Example 165.5-(8-((1S,2S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-fluoro-4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[2-fluoro-4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 432.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.72 (dd, J=6.4,2.0 Hz, 1H), 11.61 (d, J=1.9 Hz, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.22-8.06(m, 2H), 7.84 (s, 1H), 7.71-7.47 (m, 3H), 2.98 (ddt, J=39.4, 10.2, 5.4Hz, 2H), 2.13-1.90 (m, 2H).

Example 166.5-(8-((1S,2S)-2-(isoquinolin-8-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(isoquinolin-8-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]isoquinoline(racemic).ES/MS m/z: 397.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65-11.54 (m,2H), 9.80 (s, 1H), 8.65 (d, J=6.1 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H), 8.30(d, J=6.2 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.11-8.01 (m, 2H), 7.93-7.81(m, 2H), 7.74 (s, 1H), 3.56 (dt, J=8.7, 5.8 Hz, 1H), 2.90 (dt, J=8.8,5.5 Hz, 1H), 2.19 (dt, J=8.8, 5.3 Hz, 1H), 2.01 (ddd, J=8.8, 6.4, 4.8Hz, 1H).

Example 167.5-(8-((1S,2S)-2-(quinolin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(quinolin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]quinoline(racemic).ES/MS m/z: 397.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.54 (m,2H), 9.13 (d, J=5.2 Hz, 1H), 8.43-8.35 (m, 2H), 8.20 (d, J=8.5 Hz, 1H),8.07 (d, J=6.1 Hz, 1H), 7.99 (dd, J=8.4, 6.8 Hz, 1H), 7.88 (s, 1H),7.83-7.71 (m, 3H), 3.75-3.73 (m, 1H), 3.04 (dt, J=9.0, 5.7 Hz, 1H),2.40-2.30 (m, 1H), 2.17 (dt, J=8.7, 5.2 Hz, 1H).

Example 168.5-(8-((1S,2S)-2-(isoquinolin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(isoquinolin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]isoquinoline(racemic).ES/MS m/z: 397.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.64-11.54 (m,2H), 9.70 (s, 1H), 8.60 (d, J=6.4 Hz, 1H), 8.40 (d, J=1.4 Hz, 1H),8.34-8.27 (m, 2H), 8.08 (d, J=6.1 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H),7.95-7.86 (m, 2H), 7.75 (s, 1H), 3.46 (dt, J=9.0, 6.0 Hz, 1H), 2.82 (dt,J=8.9, 5.4 Hz, 1H), 2.17 (dt, J=8.9, 5.2 Hz, 1H), 1.99 (ddd, J=8.7, 6.4,4.8 Hz, 1H).

Example 169.5-(8-(3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-fluoro-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 385.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (dd, J=6.2,2.0 Hz, 1H), 11.45 (d, J=2.0 Hz, 1H), 8.21 (d, J=1.4 Hz, 1H), 8.00 (d,J=6.2 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 6.85 (s, 1H), 4.64-4.39 (m, 2H),4.12 (d, J=9.9 Hz, 1H), 4.02-3.86 (m, 1H), 2.77-2.52 (m, 2H).

Example 170.5-(8-(7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[7-(difluoromethyl)-5-azaspiro[2.4]heptan-5-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 375.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56-11.37 (m,2H), 8.20 (d, J=1.5 Hz, 1H), 8.00 (d, J=6.2 Hz, 1H), 7.82-7.74 (m, 1H),6.78 (s, 1H), 6.24 (td, J=55.8, 4.2 Hz, 1H), 4.15 (s, 2H), 3.95-3.88 (m,1H), 3.64 (s, 1H), 1.08 (dt, J=9.9, 5.5 Hz, 1H), 0.90-0.68 (m, 4H).

Example 171.5-(8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(7-fluoro-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 343.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.44-11.30 (m,2H), 8.07 (q, J=1.3 Hz, 1H), 7.95 (d, J=6.0 Hz, 1H), 7.60 (dt, J=2.4,1.4 Hz, 1H), 6.61 (t, J=2.0 Hz, 1H), 4.83 (dd, J=54.5, 3.3 Hz, 1H),4.62-3.98 (m, 3H), 3.70 (s, 1H), 1.11-0.73 (m, 4H).

Example 172. ethyl6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-8-((1S,2S)-2-(4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine-2-carboxylate

ethyl6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-8-((1S,2S)-2-(4-fluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazine-2-carboxylatewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith ethyl6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylate(racemic).ES/MS m/z: 436.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57-11.55 (m,2H), 8.75 (s, 1H), 8.02 (d, J=6.3 Hz, 1H), 7.52 (s, 1H), 7.32 (ddd,J=8.6, 5.4, 2.6 Hz, 2H), 7.20-7.09 (m, 2H), 4.34 (q, J=7.1 Hz, 2H), 2.74(dddd, J=19.7, 8.8, 6.1, 4.4 Hz, 2H), 2.01 (dt, J=9.0, 5.3 Hz, 1H),1.84-1.74 (m, 1H), 1.33 (t, J=7.1 Hz, 3H).

Example 173.5-(8-(3-(4-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(4-methoxyphenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[3-(4-methoxyphenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 405.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (d, J=6.3 Hz,1H), 11.46 (d, J=2.0 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.03 (d, J=6.2 Hz,1H), 7.90 (s, 1H), 7.38-7.28 (m, 2H), 6.94 (dd, J=9.4, 7.4 Hz, 3H), 4.33(s, 2H), 3.75 (s, 5H), 3.60-3.47 (m, 1H), 2.47-2.35 (m, 1H), 2.17-2.05(m, 1H).

Example 174.(S)-5-(8-(3-isopropylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(3-isopropylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3S)-3-isopropylpyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 341.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (d, J=6.3 Hz,1H), 11.46 (d, J=2.0 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J=6.2 Hz, 1H), 7.92(s, 1H), 6.92 (s, 1H), 4.18-3.82 (m, 2H), 3.68 (s, 1H), 3.44 (s, 1H),2.18 (dt, J=12.3, 6.3 Hz, 1H), 2.01 (p, J=8.9 Hz, 1H), 1.74-1.55 (m,2H), 0.99 (t, J=7.2 Hz, 6H).

Example 175.(R)-5-(8-(3-(trifluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3-(trifluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine.ES/MS m/z: 367.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J=6.2 Hz,1H), 11.45 (d, J=1.9 Hz, 1H), 8.24 (s, 1H), 8.01 (d, J=6.1 Hz, 1H), 7.83(s, 1H), 6.88 (s, 1H), 4.19 (t, J=10.0 Hz, 1H), 4.07-3.75 (m, 3H), 3.49(h, J=8.4 Hz, 1H), 2.37 (dtd, J=12.7, 7.6, 5.0 Hz, 1H), 2.23-2.09 (m,1H).

Example 176.5-(8-(3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 353.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.46-11.37 (m,2H), 7.97 (d, J=6.1 Hz, 1H), 7.40 (d, J=7.2 Hz, 1H), 6.63 (s, 1H), 4.37(d, J=13.8 Hz, 2H), 3.97 (d, J=7.7 Hz, 2H), 2.60 (tt, J=14.5, 7.4 Hz,2H).

Example 177.5-(8-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine.ES/MS m/z: 353.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.46-11.37 (m,2H), 7.97 (d, J=6.1 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 6.60 (s, 1H),5.60-5.50 (m, 1H), 5.47-5.37 (m, 1H), 4.27 (s, 2H), 4.00 (d, J=29.5 Hz,2H), 3.58 (s, 2H).

Example 178.5-(3-fluoro-8-((1S,2S)-2-(pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(2-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 365.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65 (dd, J=6.2,1.9 Hz, 1H), 11.56 (d, J=2.0 Hz, 1H), 8.69 (dd, J=5.6, 1.5 Hz, 1H), 8.31(t, J=8.0 Hz, 1H), 8.06 (d, J=6.2 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H), 7.72(t, J=6.6 Hz, 1H), 7.66-7.58 (m, 2H), 3.38 (dt, J=9.5, 5.5 Hz, 1H), 3.13(ddd, J=9.2, 6.4, 4.3 Hz, 1H), 2.40 (dt, J=8.6, 5.3 Hz, 1H), 2.18-2.08(m, 1H).

Example 179.5-(3-fluoro-8-((1S,2S)-2-(pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-pyrimidin-5-ylcyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 366.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62 (d, J=6.3 Hz,1H), 11.55 (d, J=1.9 Hz, 1H), 9.07 (s, 1H), 8.78 (s, 2H), 8.05 (d, J=6.1Hz, 1H), 7.68-7.57 (m, 2H), 2.91 (ddt, J=14.6, 10.6, 5.4 Hz, 2H), 2.20(dt, J=8.9, 5.5 Hz, 1H), 1.92 (dt, J=8.6, 5.4 Hz, 1H).

Example 180.5-(3-fluoro-8-((1S,2S)-2-(pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(3-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 365.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63 (dd, J=6.3,2.0 Hz, 1H), 11.55 (d, J=1.9 Hz, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.77 (dd,J=5.6, 1.2 Hz, 1H), 8.48 (dt, J=8.3, 1.6 Hz, 1H), 8.09-7.96 (m, 2H),7.60 (t, J=3.5 Hz, 2H), 3.19 (ddd, J=9.0, 6.1, 4.5 Hz, 1H), 2.96 (ddd,J=9.0, 6.2, 4.5 Hz, 1H), 2.32 (dt, J=8.9, 5.4 Hz, 1H), 1.98 (dt, J=8.8,5.4 Hz, 1H).

Example 181.5-(3-fluoro-8-((1S,2S)-2-(pyridin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(pyridin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-(4-pyridyl)cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 365.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62 (dd, J=6.3,2.0 Hz, 1H), 11.56 (d, J=2.0 Hz, 1H), 8.84-8.78 (m, 2H), 8.05 (d, J=6.2Hz, 1H), 8.02-7.95 (m, 2H), 7.64-7.55 (m, 2H), 3.24 (ddd, J=8.8, 5.9,4.2 Hz, 1H), 3.10 (ddd, J=9.1, 6.6, 4.3 Hz, 1H), 2.54 (s, 1H), 2.08 (dt,J=9.0, 5.3 Hz, 1H).

Example 182.5-(8-((1S,2S)-2-(4-chlorophenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-chlorophenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-[(1S,2S)-2-(4-chlorophenyl)cyclopropyl]-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 398.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.51 (m,2H), 8.04 (d, J=6.2 Hz, 1H), 7.62 (d, J=6.9 Hz, 1H), 7.51 (s, 1H),7.40-7.32 (m, 2H), 7.29 (d, J=8.6 Hz, 2H), 2.83 (ddd, J=9.0, 6.2, 4.4Hz, 1H), 2.76-2.66 (m, 1H), 2.08 (dt, J=8.8, 5.3 Hz, 1H), 1.75 (ddd,J=8.7, 6.3, 4.9 Hz, 1H).

Example 183.5-(3-fluoro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-[(1S,2S)-2-[4-(trifluoromethyl)phenyl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 432.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (dd, J=10.4,4.1 Hz, 2H), 8.04 (d, J=6.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 2H), 7.58 (d,J=7.0 Hz, 1H), 7.54-7.46 (m, 3H), 2.95 (ddd, J=9.0, 6.2, 4.4 Hz, 1H),2.84-2.74 (m, 1H), 2.18 (dt, J=8.7, 5.3 Hz, 1H), 1.83 (dt, J=8.6, 5.2Hz, 1H).

Example 184.5-(8-((1S,2S)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-1-methyl-pyridin-2-one(racemic).ES/MS m/z: 377.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.69-11.62 (m,1H), 11.59 (d, J=1.9 Hz, 1H), 8.47 (s, 1H), 8.12-8.04 (m, 2H), 7.72 (d,J=2.6 Hz, 1H), 7.67 (s, 1H), 7.37 (dd, J=9.4, 2.6 Hz, 1H), 6.39 (d,J=9.3 Hz, 1H), 3.41 (s, 3H), 2.74-2.66 (m, 1H), 2.55 (t, J=5.5 Hz, 1H),1.87 (dt, J=9.0, 5.3 Hz, 1H), 1.73 (dt, J=8.4, 5.5 Hz, 1H).

Example 185.5-[8-[3-methyl-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), 3-methyl-3-(trifluoromethyl)pyrrolidine;hydrochloride (40 mg, mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42 mmol,2.6 equiv) in NMP (1 mL) was heated at 100° C. After 4 h, the reactionmixture was directly purified by RP-HPLC (5-75% MeCN/H₂O with TFAmodifier), affording5-[8-[3-methyl-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 381.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43-11.33 (m,2H), 8.05 (s, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.57 (s, 1H), 6.61 (s, 1H),4.26-3.99 (m, 4H), 2.41-2.29 (m, 1H), 2.06 (ddd, J=13.0, 7.9, 5.2 Hz,1H), 1.37 (s, 3H).

Example 186.5-[8-[(3R)-3-fluoro-3-methyl-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), (3R)-3-fluoro-3-methyl-pyrrolidine;hydrochloride (29.5 mg, 0.21 mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42mmol, 2.6 equiv) in NMP (1 mL) was heated at 100° C. After 4 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording5-[8-[(3R)-3-fluoro-3-methyl-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 331.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (dd, J=12.4,4.1 Hz, 2H), 8.05 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.58 (t,J=1.4 Hz, 1H), 6.60 (d, J=2.3 Hz, 1H), 4.57-3.71 (m, 4H), 2.38-2.06 (m,2H), 1.62 (d, J=20.9 Hz, 3H).

Example 187.5-[8-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), (3R)-3-(trifluoromethoxy)pyrrolidine;hydrochloride (40.4 mg, mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42mmol, 2.6 equiv) in NMP (1 mL) was heated at 100° C. After 4 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording5-[8-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 383.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (dd, J=14.7,4.1 Hz, 2H), 8.04 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.56 (d,J=1.2 Hz, 1H), 6.61 (s, 1H), 5.30 (d, J=4.0 Hz, 1H), 4.40-4.14 (m, 4H),2.32 (s, 2H).

Example 188.5-[8-[3-fluoro-3-(methoxymethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), 3-fluoro-3-(methoxymethyl)pyrrolidine;hydrochloride (36 mg, mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42 mmol,2.6 equiv) in NMP (1 mL) was heated at 130° C. After 2 h, the reactionmixture was directly purified by RP-HPLC (5-75% MeCN/H₂O with TFAmodifier), affording5-[8-[3-fluoro-3-(methoxymethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 361.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43-11.33 (m,2H), 8.04 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.57 (d, J=1.1 Hz,1H), 6.60 (s, 1H), 4.04-3.71 (m, 6H), 3.39 (s, 3H), 2.31-2.13 (m, 2H).

Example 189.5-[8-[3-methoxy-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), 3-methoxy-3-(trifluoromethyl)pyrrolidine;hydrochloride (43.4 mg, 0.21 mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42mmol, 2.6 equiv) in NMP (1 mL) was heated at 100° C. After 4 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording5-[8-[3-methoxy-3-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 397.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.39 (dd, J=14.1,4.0 Hz, 2H), 8.05 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.57 (d,J=1.1 Hz, 1H), 6.62 (s, 1H), 4.56 (s, 2H), 4.14 (d, J=12.9 Hz, 2H), 3.42(s, 3H), 2.44-2.33 (m, 2H)

Example 190.5-[8-(5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), 5-azaspiro[2.4]heptane (20.5 mg, 0.21 mmol, 1.3equiv), and DIPEA (0.043 mL, 0.25 mmol, 1.5 equiv) in NMP (1 mL) washeated at 130° C. After 2 h, the reaction mixture was directly purifiedby RP-HPLC (5-75% MeCN/H₂O with TFA modifier), affording5-[8-(5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 325.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41-11.33 (m,2H), 8.05 (d, J=1.3 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.3 Hz,1H), 6.60 (s, 1H), 3.87-3.80 (m, 4H), 1.95 (t, J=6.9 Hz, 2H), 0.74-0.61(m, 4H).

Example 191.5-[8-[(3S)-3-fluoro-3-methyl-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), (3S)-3-fluoro-3-methyl-pyrrolidine;hydrochloride (29.5 mg, 0.21 mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42mmol, 2.6 equiv) in NMP (1 mL) was heated at 100° C. After 4 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording5-[8-[(3S)-3-fluoro-3-methyl-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 331.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43-11.31 (m,2H), 8.05 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.2 Hz,1H), 6.60 (s, 1H), 4.10-3.71 (m, 4H), 2.36-2.06 (m, 2H), 1.62 (d, J=20.9Hz, 3H).

Example 192.5-[8-(5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), 2,2-difluoro-5-azaspiro[2.4]heptane;hydrochloride (36 mg, 0.21 mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42mmol, 2.6 equiv) in NMP (1 mL) was heated at 130° C. After 2 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording5-[8-(5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 361.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43-11.30 (m,2H), 8.05 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.57 (d, J=1.2 Hz,1H), 6.62 (s, 1H), 4.28-3.85 (m, 4H), 2.21 (ddt, J=33.2, 12.5, 6.2 Hz,2H), 1.74 (dddd, J=41.4, 13.3, 8.4, 4.6 Hz, 2H).

Example 193.5-[8-[(3S,4S)-3-methyl-4-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv),(3S,4S)-3-methyl-4-(trifluoromethyl)pyrrolidine; hydrochloride (40 mg,0.21 mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42 mmol, 2.6 equiv) in NMP(1 mL) was heated at 100° C. After 4 h, the reaction mixture wasdirectly purified by RP-HPLC (5-75% MeCN/H₂O with TFA modifier),affording5-[8-[(3S,4S)-3-methyl-4-(trifluoromethyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 381.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43-11.33 (m,2H), 8.04 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.57 (d, J=1.1 Hz,1H), 6.60 (s, 1H), 4.30-4.01 (m, 4H), 3.11 (h, J=8.7 Hz, 1H), 2.59 (p,J=7.6 Hz, 1H), 1.21 (d, J=6.6 Hz, 3H).

Example 194.5-[8-[3,3-difluoro-4-(4-methoxyphenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), 3,3-difluoro-4-(4-methoxyphenyl)pyrrolidine;hydrochloride (52.7 mg, 0.21 mmol, 1.3 equiv), and DIPEA (0.073 mL, 0.42mmol, 2.6 equiv) in NMP (1 mL) was heated at 100° C. After 4 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording5-[8-[3,3-difluoro-4-(4-methoxyphenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 441.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.44-11.35 (m,2H), 8.09 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.59 (d, J=1.1 Hz,1H), 7.39-7.27 (m, 2H), 7.03-6.94 (m, 2H), 6.67 (s, 1H), 4.52-4.47 (m,3H), 4.12-4.10 (m, 2H), 3.33 (s, 3H).

Example 195.1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-3-fluoro-pyrrolidine-3-carbonitrile

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (100mg, 0.325 mmol, 1 equiv), 3-fluoropyrrolidine-3-carbonitrile;hydrochloride (63.5 mg, 0.42 mmol, 1.3 equiv), and DIPEA (0.153 mL, 0.84mmol, 2.6 equiv) in NMP (1 mL) was heated at 100° C. After 16 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-3-fluoro-pyrrolidine-3-carbonitrile.ES/MS m/z: 342.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.40 (dd, J=14.1,4.2 Hz, 2H), 8.08 (d, J=1.2 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.59 (d,J=1.2 Hz, 1H), 6.64 (s, 1H), 4.92 (s, 2H), 4.47 (dd, J=34.8, 13.6 Hz,1H), 4.10 (s, 1H), 3.81 (d, J=10.0 Hz, 1H), 2.91-2.66 (m, 2H).

Example 196.5-[8-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (45mg, 0.15 mmol, 1 equiv), (3S)-3-(trifluoromethoxy)pyrrolidine;hydrochloride (36 mg, 0.19 mmol, 1.3 equiv), and DIPEA (0.066 mL, 0.38mmol, 2.6 equiv) in NMP (1 mL) was heated at 100° C. After 4 h, thereaction mixture was directly purified by RP-HPLC (5-75% MeCN/H₂O withTFA modifier), affording5-[8-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 383.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.42-11.33 (m,2H), 8.05 (s, 1H), 7.94 (d, J=5.9 Hz, 1H), 7.58 (s, 1H), 6.62 (s, 1H),5.30 (s, 1H), 4.14 (d, J=12.8 Hz, 1H), 3.95 (s, 1H), 3.78 (s, 1H),2.41-2.26 (m, 2H).

Example 197.6-(2,4-dioxo-1H-pyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]-N,N-dimethyl-imidazo[1,2-b]pyridazine-2-carboxamide(Racemic Mixture)

Step 1: To a solution of ethyl6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylate(50 mg, 0.108 mmol, 1 equiv) in THF (3 mL) was added 1 ml methanol and2M aqueous lithium hydroxide solution (0.27 mL, 0.539 mmol, 5 equiv).After stirring for 1 h at room temperature, the reaction mixture wasconcentrated. Residue obtained was dissolved in water and neutralizedwith 1N HCl. Solids separated were filtered and dried at high vacuumovernight affording6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylicacid. ES/MS m/z: 436.20 [M+H].

Step 2: To a solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylicacid (45 mg, 0.103 mmol, 1 equiv) in DMF (2 mL) was added HATU (157 mg,0.413 mmol, 4 equiv), N,N-Diisopropylethylamine (0.07 mL, 0.41 mmol, 4equiv) and Dimethylamine solution/2M THF (0.41 mL, 0.83 mmol, 8 equiv).After stirring for 3 h at room temperature, the reaction mixture wasquenched with methanol and purified with RP-HPLC (10-90% MeCN/H₂O withTFA modifier) affording6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]-N,N-dimethyl-imidazo[1,2-b]pyridazine-2-carboxamide.ES/MS m/z: 463.20 [M+H].

Step 3: A solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]-N,N-dimethyl-imidazo[1,2-b]pyridazine-2-carboxamide(35 mg) in 1:1 1N HCl:MeOH (3 mL) was heated to 80° C. After 6 hours,the solids separated was filtered, washed with acetonitrile and dried athigh vacuum overnight to afford6-(2,4-dioxo-1H-pyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]-N,N-dimethyl-imidazo[1,2-b]pyridazine-2-carboxamide.ES/MS m/z: 435.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 2H), 8.48(d, J=1.7 Hz, 1H), 8.01 (d, J=6.2 Hz, 1H), 7.55 (s, 1H), 7.36-7.27 (m,2H), 7.14 (t, J=8.7 Hz, 2H), 3.38 (s, 3H), 3.02 (s, 3H), 2.89 (dd,J=9.1, 5.3 Hz, 1H), 2.63 (dt, J=10.0, 5.5 Hz, 1H), 2.12 (dt, J=9.9, 5.6Hz, 1H), 1.74 (dt, J=8.0, 5.6 Hz, 1H).

Example 198.5-[2-(3,3-difluoroazetidine-1-carbonyl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione(Racemic Mixture)

Step 1: To a solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylicacid (50 mg, 0.115 mmol, 1 equiv) in DMF (2 mL) was added HATU (218 mg,0.574 mmol, 5 equiv), N,N-Diisopropylethylamine (0.1 mL, 0.574 mmol, 5equiv) and 3,3-difluoroazetidine hydrochloride (59 mg, 0.46 mmol, 4equiv). After stirring for 3 h at room temperature, the reaction mixturewas quenched with methanol and purified with RP-HPLC (15-90% MeCN/H₂Owith TFA modifier) affording(3,3-difluoroazetidin-1-yl)-[6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-2-yl]methanone.ES/MS m/z: 511.20 [M+H].

Step 2: A solution of(3,3-difluoroazetidin-1-yl)-[6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-2-yl]methanone(50 mg) in 1:1 1N HCl:MeOH (3 mL) was heated to 80° C. After 6 hours,the solids separated was filtered, washed with acetonitrile and dried athigh vacuum overnight to afford5-[2-(3,3-difluoroazetidine-1-carbonyl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 483.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 2H), 8.66(s, 1H), 8.02 (s, 1H), 7.63 (s, 1H), 7.38-7.28 (m, 2H), 7.21-7.06 (m,2H), 5.03 (p, J=12.4 Hz, 2H), 4.51 (t, J=12.6 Hz, 2H), 3.01 (dd, J=6.3,3.1 Hz, 1H), 2.63 (dt, J=9.0, 5.4 Hz, 1H), 2.33-2.17 (m, 1H), 1.74-1.68(m, 1H).

Example 199.5-[2-(3,3-difluoropyrrolidine-1-carbonyl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione(Racemic Mixture)

Step 1: To a solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylicacid (50 mg, 0.115 mmol, 1 equiv) in DMF (2 mL) was added HATU (218 mg,0.574 mmol, 5 equiv), N,N-Diisopropylethylamine (0.1 mL, 0.574 mmol, 5equiv) and 3,3-difluoropyrolidine hydrochloride (49.5 mg, 0.345 mmol, 3equiv). After stirring for 3 h at room temperature, the reaction mixturewas quenched with methanol and purified with RP-HPLC (15-90% MeCN/H₂Owith TFA modifier) affording(3,3-difluoropyrrolidin-1-yl)-[6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-2-yl]methanone.ES/MS m/z: 525.20 [M+H].

Step 2: A solution of((3,3-difluoropyrrolidin-1-yl)-[6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-2-yl]methanone(51 mg) in 1:1 1N HCl:MeOH (3 mL) was heated to 80° C. After 6 hours,the solids separated was filtered, washed with acetonitrile and dried athigh vacuum overnight to afford5-[2-(3,3-difluoropyrrolidine-1-carbonyl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 497.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 2H), 8.62(s, 1H), 8.02 (d, J=4.9 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.32 (ddd,J=8.9, 5.5, 3.3 Hz, 2H), 7.14 (t, J=8.8 Hz, 2H), 4.55-4.45 (m, 1H), 4.30(td, J=7.4, 2.8 Hz, 1H), 4.08-3.86 (m, 1H), 3.77 (t, J=7.5 Hz, 1H),3.08-2.87 (m, OH), 2.72-2.55 (m, 1H), 2.43 (dd, J=14.4, 7.2 Hz, 1H),2.22-2.14 (m, 1H), 1.74 (ddd, J=8.8, 6.4, 4.8 Hz, 1H).

Example 200.5-[2-[(3S,4R)-3,4-difluoropyrrolidine-1-carbonyl]-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione(Racemic Mixture)

Step 1: To a solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazine-2-carboxylicacid (50 mg, 0.115 mmol, 1 equiv) in DMF (2 mL) was added HATU (218 mg,0.574 mmol, 5 equiv), N,N-Diisopropylethylamine (0.1 mL, 0.574 mmol, 5equiv) and (3S,4R)-3,4-difluoropyrrolidine; hydrochloride (49.5 mg,0.345 mmol, 3 equiv). After stirring for 3 h at room temperature, thereaction mixture was quenched with methanol and purified with RP-HPLC(15-90% MeCN/H₂O with TFA modifier) affording[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-[6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-2-yl]methanone.ES/MS m/z: 525.20 [M+H].

Step 2: A solution of[(3S,4R)-3,4-difluoropyrrolidin-1-yl]-[6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-2-yl]methanone(50 mg) in 1:1 1N HCl:MeOH (3 mL) was heated to 80° C. After 6 hours,the solids separated was filtered, washed with acetonitrile and dried athigh vacuum overnight to afford5-[2-[(3S,4R)-3,4-difluoropyrrolidine-1-carbonyl]-8-[(1S,2S)-2-(4-fluorophenyl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 497.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 2H), 8.62(s, 1H), 8.02 (s, 1H), 7.62 (d, J=3.7 Hz, 1H), 7.33 (ddd, J=8.5, 5.4,2.7 Hz, 2H), 7.14 (td, J=8.8, 1.3 Hz, 2H), 5.40 (ddd, J=49.4, 11.9, 6.3Hz, 2H), 4.51 (ddt, J=19.9, 13.3, 6.4 Hz, 1H), 4.30-4.07 (m, 1H),4.06-3.65 (m, 2H), 2.98 (td, J=9.9, 9.1, 5.1 Hz, 1H), 2.62 (tt, J=9.1,4.1 Hz, 1H), 2.19 (dt, J=10.0, Hz, 1H), 1.74 (dtd, J=8.8, 4.8, 2.6 Hz,1H).

Example 201.5-[8-[(4S)-4-(difluoromethoxy)-3,3-difluoro-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

Step 1: A microwave vial was charged with(3S)-4,4-difluoropyrrolidin-3-ol; hydrochloride (289 mg, 1.81 mmol, 1.3equiv), DIPEA (0.73 mL, 4.17 mmol, 3 equiv), and NMP (2 mL) then6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine(500 mg, 1.39 mmol, 1 equiv). The reaction mixture was heated to 100° C.for 2 hour. The mixture was cooled diluted with EtOAc and water and thelayers separated. The organic layer was dried over sodium sulfate,concentrated and purified by flash column chromatography to give(3S)-1-[6-(2,4-ditert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol.ES/MS m/z: 463.10 [M+H].

Step 2:(3S)-1-[6-(2,4-ditert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(100 mg, 0.216 mmol, 1 equiv) and sodium hydride (60% dispersion in oil,25 mg, 0.65 mmol, 3 equiv) were combined in THF (2 mL) at 5° C. After 15minutes, difluoro(iodo)methane (5.41 mL, 0.54 mmol, 2.5 equiv) wasadded. After stirring at 0° C. for 6 h, the reaction was treated withwater (0.2 mL) and TFA (0.2 mL), concentrated to dryness, then purifiedby RP-HPLC (10-70% MeCN/H₂O gradient with TFA modifier) affording5-[8-[(4S)-4-(difluoromethoxy)-3,3-difluoro-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 401.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41 (dd, J=13.2,4.1 Hz, 2H), 8.09 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.59 (d,J=1.1 Hz, 1H), 7.16 (s, OH), 6.98 (s, OH), 6.80 (s, OH), 6.62 (s, 1H),5.25 (q, J=7.4, 6.6 Hz, 1H), 4.41 (q, J=15.4 Hz, 3H), 4.06 (d, J=12.2Hz, 1H), 3.45 (q, J=7.0 Hz, 1H).

Example 202.5-[8-[4-(difluoromethoxy)-3,3-difluoro-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

Step 1:1-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(75 mg, 0.198 mmol, 1 equiv) and sodium hydride (60% dispersion in oil,23 mg, mmol, 3 equiv) were combined in THF (2 mL) at 5° C. After 15minutes, difluoro(iodo)methane (4.96 mL, 0.496 mmol, 2.5 equiv) wasadded. After stirring at 0° C. for 6 h, the reaction was treated withwater (0.2 mL) purified by flash column chromatography usingethylacetate/hexanes, affording8-[4-(difluoromethoxy)-3,3-difluoro-pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 429.10 [M+H].

Step 2: A solution of8-[4-(difluoromethoxy)-3,3-difluoro-pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(21 mg) in 1:1 1N HCl:MeOH (5 mL) was heated to 80° C. After 2 hours,the reaction mixture was concentrated and residue obtained was purifiedby RP-HPLC (5-80% MeCN/H₂O gradient with TFA modifier) affording5-[8-[4-(difluoromethoxy)-3,3-difluoro-pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 401.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.36 (m,2H), 8.09 (s, 1H), 7.95 (d, J=5.9 Hz, 1H), 7.60 (s, 1H), 7.16 (s, OH),6.98 (s, OH), 6.80 (s, OH), 6.63 (s, 1H), 5.31-5.22 (m, 1H), 4.39 (t,J=15.0 Hz, 3H), 4.06 (d, J=11.8 Hz, 1H).

Example 203.8-[3,3-difluoro-4-(2,2,2-trifluoroethoxy)pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine

Step 1:1-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(50 mg, 0.132 mmol, 1 equiv) and sodium hydride (60% dispersion in oil,15 mg, mmol, 3 equiv) were combined in THF (2 mL) at 5° C. After 15minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate (61.3 mg, 0.264mmol, 2 equiv) was added. After stirring at 0° C. for 6 h, the reactionwas treated with water (0.2 mL) purified by flash column chromatographyusing 0-100% ethylacetate/hexanes, affording8-[3,3-difluoro-4-(2,2,2-trifluoroethoxy)pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 461.20 [M+H].

Step 2: A solution of8-[3,3-difluoro-4-(2,2,2-trifluoroethoxy)pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(15 mg) in 1:1 1N HCl:MeOH (5 mL) was heated to 80° C. After 2 hours,the reaction mixture was concentrated and residue obtained was purifiedby RP-HPLC (5-80% MeCN/H₂O gradient with TFA modifier) affording8-[3,3-difluoro-4-(2,2,2-trifluoroethoxy)pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 433.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.35 (m,2H), 8.08 (d, J=1.1 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.1 Hz,1H), 6.61 (s, 1H), 4.73-4.62 (m, 1H), 4.57-4.18 (m, 4H), 4.06 (s, 1H).

Example 204.2-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]oxy-N,N-dimethyl-acetamide

1-[6-(2,4-ditert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-ol(80 mg, 0.173 mmol, 1 equiv) and sodium hydride (60% dispersion in oil,20 mg, 0.52 mmol, 3 equiv) were combined in THF (2 mL) at 5° C. After 15minutes, 2-bromo-N,N-dimethyl-acetamide (57.4 mg, 0.346 mmol, 2 equiv)was added. After stirring at 0° C. for 1 h, the reaction was treatedwith 1M HCl (0.2 mL), concentrated to dryness, then purified by RP-HPLC(5-80% MeCN/H₂O gradient with TFA modifier) affording2-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]oxy-N,N-dimethyl-acetamide.ES/MS m/z: 436.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.46-11.35 (m,2H), 8.08 (s, 1H), 7.95 (d, J=6.0 Hz, 1H), 7.58 (s, 1H), 6.61 (s, 1H),4.54-4.09 (m, 7H), 2.87 (d, J=25.8 Hz, 6H).

Example 205.N-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]acetamide

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (70 mg,0.16 mmol, 1 equiv), N-(4,4-difluoropyrrolidin-3-yl)acetamide;hydrochloride (91 mg, 0.454 mmol, 2 equiv), and DIPEA (0.16 mL, 0.91mmol, 4 equiv) in NMP (1 mL) was heated at 110° C. After 6 h, thereaction mixture was directly purified by RP-HPLC (5-70% MeCN/H₂O withTFA modifier), affordingN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]acetamide.ES/MS m/z: 392.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.31 (m,2H), 8.50 (d, J=8.6 Hz, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.95 (d, J=6.1 Hz,1H), 7.59 (d, J=1.2 Hz, 1H), 6.62 (s, 1H), 5.00-4.84 (m, 1H), 4.39 (t,J=27.3 Hz, 3H), 3.85-3.65 (m, 1H), 1.92 (d, J=3.2 Hz, 3H).

Example 206. 2,2,2-trifluoroethylN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]carbamate

A microwave vial was charged with 2,2,2-trifluoroethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride (71 mg, 0.25mmol, 2 equiv), DIPEA (0.09 mL, 0.50 mmol, 4 equiv), and NMP (2 mL) then6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine(45 mg, 0.125 mmol, 1 equiv). The reaction mixture was heated to 100° C.for 3 hours. The mixture was purified by RP-HPLC (5-80% MeCN/H₂O withTFA modifier), to give 2,2,2-trifluoroethylN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]carbamate.ES/MS m/z: 476.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.52-11.30 (m,2H), 8.50 (d, J=8.7 Hz, 1H), 8.08 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz,1H), 7.62-7.56 (m, 1H), 6.61 (s, 1H), 4.75 (q, J=9.1 Hz, 3H), 4.39 (d,J=32.5 Hz, 3H), 3.76 (d, J=38.3 Hz, 1H).

Example 207. cyclopropylmethylN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]carbamate

A microwave vial was charged with cyclopropylmethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride (50 mg, 0.20mmol, 2 equiv), DIPEA (0.07 mL, 0.39 mmol, 4 equiv), and NMP (2 mL) then6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine(35 mg, 0.1 mmol, 1 equiv). The reaction mixture was heated to 100° C.for 2 hours. The mixture was purified by RP-HPLC (5-80% MeCN/H₂O withTFA modifier), affording cyclopropylmethylN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]carbamate.ES/MS m/z: 448.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.50-11.33 (m,2H), 8.07 (d, J=1.1 Hz, 1H), 7.96 (dd, J=7.8, 5.4 Hz, 2H), 7.58 (d,J=1.2 Hz, 1H), 6.60 (s, 1H), 4.72 (dt, J=15.2, 8.0 Hz, 1H), 4.37 (d,J=48.8 Hz, 3H), 3.94-3.68 (m, 3H), 1.18-1.08 (m, 1H), 0.58-0.48 (m, 2H),0.35-0.24 (m, 2H).

Example 208. 2,2-difluoroethylN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]carbamate

A microwave vial was charged with 2,2-difluoroethylN-(4,4-difluoropyrrolidin-3-yl)carbamate; hydrochloride (46 mg, 0.17mmol, 2 equiv), DIPEA (0.06 mL, 0.33 mmol, 4 equiv), and NMP (2 mL) then6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-fluoroimidazo[1,2-b]pyridazine(30 mg, 0.08 mmol, 1 equiv). The reaction mixture was heated to 100° C.for 3 hours. The mixture was purified by RP-HPLC (5-80% MeCN/H₂O withTFA modifier), to give 2,2-difluoroethylN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]carbamate.ES/MS m/z: 458.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.46-11.36 (m,2H), 8.32 (d, J=8.7 Hz, 1H), 8.08 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz,1H), 7.58 (d, J=1.1 Hz, 1H), 6.61 (s, 1H), 6.27 (tt, J=54.3, 3.3 Hz,1H), 4.73 (dq, J=16.1, 8.2 Hz, 1H), 4.52-4.29 (m, 5H), 3.86-3.70 (m,1H).

Example 209.N-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]benzamide

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (70 mg,0.23 mmol, 1 equiv), N-(4,4-difluoropyrrolidin-3-yl)benzamide;hydrochloride (119 mg, 0.454 mmol, 2 equiv), and DIPEA (0.16 mL, 0.91mmol, 4 equiv) in NMP (1 mL) was heated at 110° C. After 6 h, thereaction mixture was directly purified by RP-HPLC (5-80% MeCN/H₂O withTFA modifier), affordingN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]benzamide.ES/MS m/z: 454.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.36 (m,2H), 8.91 (d, J=8.4 Hz, 1H), 8.08 (s, 1H), 7.99-7.88 (m, 3H), 7.63-7.52(m, 2H), 7.50 (t, J=7.5 Hz, 2H), 6.65 (s, 1H), 5.26-5.16 (m, 1H), 4.52(s, 3H), 4.02 (s, 1H)

Example 210.N-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]-4-(trifluoromethyl)benzamide

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (70 mg,0.23 mmol, 1 equiv),N-(4,4-difluoropyrrolidin-3-yl)-4-(trifluoromethyl)benzamide;hydrochloride (140 mg, 0.424 mmol, 1.9 equiv), and DIPEA (0.16 mL, 0.91mmol, 4 equiv) in NMP (1 mL) was heated at 110° C. After 6 h, thereaction mixture was directly purified by RP-HPLC (5-80% MeCN/H₂O withTFA modifier), affordingN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]-4-(trifluoromethyl)benzamide.ES/MS m/z: 522.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41 (d, J=14.6Hz, 2H), 9.16 (d, J=8.3 Hz, 1H), 8.15-8.03 (m, 3H), 7.93 (dd, J=25.6,7.1 Hz, 3H), 7.59 (s, 1H), 6.65 (s, 1H), 5.26-5.17 (m, 1H), 4.53 (s,2H), 4.40 (s, 1H), 4.04 (s, 1H).

Example 211.N-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]-5-(trifluoromethyl)pyridine-2-carboxamide

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (70 mg,0.23 mmol, 1 equiv),N-(4,4-difluoropyrrolidin-3-yl)-5-(trifluoromethyl)pyridine-2-carboxamide;hydrochloride (151 mg, 0.45 mmol, 2 equiv), and DIPEA (0.16 mL, 0.91mmol, 4 equiv) in NMP (1 mL) was heated at 110° C. After 6 h, thereaction mixture was directly purified by RP-HPLC (5-80% MeCN/H₂O withTFA modifier), affordingN-[1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]-5-(trifluoromethyl)pyridine-2-carboxamide.ES/MS m/z: 523.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.36 (m,2H), 9.54 (d, J=8.9 Hz, 1H), 9.13-9.05 (m, 1H), 8.48 (dd, J=8.2, 2.3 Hz,1H), 8.29 (d, J=8.2 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.96 (d, J=6.1 Hz,1H), 7.59 (d, J=1.2 Hz, 1H), 6.65 (s, 1H), 5.24 (q, J=9.4 Hz, 1H), 5.09(s, OH), 4.54 (s, 2H), 4.42 (s, 1H), 4.12 (s, 1H).

Example 212.5-[3-chloro-8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

Step 1: A solution of6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one(racemic Mixture) (48 mg) in 1:1 1N HCl:MeOH (10 mL) was heated to 80°C. After 4 hours, the reaction mixture was concentrated and residueobtained was diluted with water and acetonitrile and lyophilized,affording5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione(racemic mixture). ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d, J=7.0 Hz, 2H),8.36 (d, J=1.4 Hz, 1H), 8.04 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.58 (s,1H), 7.33 (d, J=7.6 Hz, 1H), 7.14 (s, 1H), 7.00 (dd, J=7.8, 1.4 Hz, 1H),4.63 (q, J=9.4 Hz, 2H), 2.83 (ddd, J=9.2, 6.3, 4.4 Hz, 1H), 2.75 (dt,J=9.6, 5.4 Hz, 1H), 2.07 (dt, J=8.9, 5.2 Hz, 1H), 1.90-1.80 (m, 1H),1.30 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −69.28 (t, J=9.4 Hz), −75.24

Step 2: Palau' Chlor (20 mg, 0.095 mmoL, 1 equiv) was added to asolution of5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;hydrochloride (racemic mixture) (52 mg, 0.095 mmol, 1 equiv) in DMF (1mL). After 16 h, the reaction mixture was directly purified by RP-HPLC(10-80% MeCN/H₂O with TFA modifier), affording5-[3-chloro-8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione(racemic mixture). ES/MS m/z: 545.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.58-11.50 (m, 2H), 8.08-8.01 (m, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.31(d, J=7.6 Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J=7.7, 1.5 Hz, 1H), 4.63 (q,J=9.4 Hz, 2H), 2.86 (dt, J=9.3, 5.8 Hz, 1H), 2.76 (dd, J=8.9, 5.1 Hz,1H), 2.17-2.06 (m, 1H), 1.87-1.74 (m, 1H), 1.30 (s, 6H). ¹⁹F NMR (376MHz, DMSO-d6) δ −69.31 (t, J=9.3 Hz), −74.69.

Example 213.5-[3-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

Palau' Chlor (11 mg, 0.05 mmoL, 1 equiv) was added to a solution of5-[8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;2,2,2-trifluoroacetic acid (racemic mixture) (30 mg, 0.05 mmol, 1 equiv)in DMF (1 mL). After 1 h, the reaction mixture was directly purified byRP-HPLC (15-95% MeCN/H₂O with TFA modifier), affording5-[3-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 520.10 [M+H]. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.24 (s,2H), 8.13 (d, J=6.4 Hz, 1H), 7.78 (d, J=4.3 Hz, 2H), 7.66 (d, J=8.5 Hz,1H), 7.45 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.5, 1.3 Hz, 1H), 4.98 (q,J=8.7 Hz, 2H), 2.98-2.78 (m, 2H), 2.11 (dt, J=9.1, 5.7 Hz, 1H), 1.90(dt, J=8.9, 5.8 Hz, 1H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −72.34 (t,J=8.8 Hz), —77.32, −135.42 (d, J=2.1 Hz).

Example 214.5-[8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

SelectFluor (253 mg, 0.71 mmoL, 1 equiv) was added to a solution of5-[8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;2,2,2-trifluoroacetic acid (racemic mixture) (310 mg, 0.55 mmol, 1equiv) in DMF (10 mL). After 16 h, the reaction mixture was directlypurified by RP-HPLC (15-95% MeCN/H₂O with TFA modifier), affording5-[8-[(1S,2S)-2-[1-(2,2-difluoroethyl)indazol-6-yl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione(racemic mixture). ES/MS m/z: 468.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.53 (d, J=4.6 Hz, 2H), 8.14-8.02 (m, 2H), 7.78-7.63 (m, 2H), 7.61-7.46(m, 2H), 7.08 (dd, J=8.4, 1.4 Hz, 1H), 6.61-6.25 (m, 1H), 4.91 (td,J=15.0, 3.8 Hz, 2H), 3.02 (ddd, J=9.1, 6.2, 4.4 Hz, 1H), 2.79 (dt,J=9.6, 5.5 Hz, 1H), 2.17 (dt, J=8.7, 5.2 Hz, 1H), 1.90 (dt, J=8.7, 5.5Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.68, −122.27 (t, J=15.0 Hz),−122.41 (t, J=15.1 Hz), −155.59 (d, J=7.4 Hz).

Example 215.5-(7-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: A microwave vial was charged with (33 mg, 0.090mmol, 1 equiv), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (29 mg,0.108 mmol, 1.2 equiv), Pd(dppf)Cl₂CH₂Cl₂ (7 mg, 0.009 mmol, 0.1 equiv)and cesium carbonate (88 mg, mmol, 3 equiv). To this was added 1,4dioxane (2.0 mL) and water (0.50 mL). The reaction mixture was heated to90° C. and stirred overnight. After cooling to room temperature, themixture was diluted with EtOAc and filtered through a pad of Celite. Thefiltrate was concentrated under reduced pressure and the crude materialwas purified by silica gel chromatography (0-100% EtOAc in hexanes),then by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) to affordthe title compound as the TFA salt. ES/MS m/z: 396.0 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.64-11.48 (m, 2H), 8.34 (d, J=6.3 Hz, 1H), 8.16 (d,J=2.3 Hz, 1H), 7.68 (s, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz,2H), 7.01 (t, J=56.0 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 3.14-3.05 (m, 1H),2.72-2.61 (m, 1H), 1.98-1.79 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.10, −109.35.

Example 216:5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine(110 mg, mmol, 1 equiv) in MeOH (2.5 mL) was added 1 N HCl (2.5 mL). Thesolution was heated to 80° C. and stirred for 25 min. The heat wasturned off and the solution was left to stir overnight. The mixture waspurified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) toafford the title compound as the TFA. ES/MS m/z: 363.1 [M+H]. ¹H NMR(400 MHz, DMSO-d6) δ 11.65 (s, 1H), 11.52 (s, 1H), 8.38 (d, J=6.0 Hz,1H), 8.07 (s, 1H), 7.00 (s, 1H), 6.41 (s, 1H), 4.59 (t, J=13.7 Hz, 2H),3.91 (s, 2H), 1.22 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.85,−115.20.

Example 217:5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-ethylpyrazolo[1,5-a]pyrimidine(60 mg, 0.143 mmol, 1 equiv) in MeOH (1.5 mL) was added 1 N HCl (1.5mL). The solution was heated to 80° C. and stirred for 3 h prior topurification by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) toafford the title compound as the TFA salt. ES/MS m/z: 391.1 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.75-11.45 (m, 2H), 8.40 (d, J=5.9 Hz, 1H),7.98 (s, 1H), 6.92 (s, 1H), 4.58 (t, J=13.8 Hz, 2H), 3.90 (s, 2H), 2.67(q, J=7.6 Hz, 2H), 1.27-1.18 (m, 9H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.18, −115.17.

Example 218:5-(3-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of3-chloro-7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine(32 mg, 0.077 mmol, 1 equiv) in MeOH (2.0 mL) was added 1 N HCl (2.0mL). The solution was heated to 80° C. and stirred for 2 h prior toisolation by filtration as the HCl salt. ES/MS m/z: 395.0 [M+H]. ¹H NMR(400 MHz, DMSO-d6) δ 11.55 (d, J=6.4 Hz, 1H), 11.47 (s, 1H), 8.40 (d,J=6.3 Hz, 1H), 8.19 (s, 1H), 7.21 (s, 1H), 4.64 (t, J=12.5 Hz, 2H), 4.06(s, 2H), 1.08-1.00 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −107.33.

Examples 219 and 220.5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneand5-(3-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneand5-(3-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneas the TFA salts were prepared in the manner described for Example 1,but replacing7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewith a mixture of7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-fluoropyrazolo[1,5-a]pyrimidineand3-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine.

Example 219:5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneES/MS m/z: 381.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58-11.43 (m, 2H),8.35 (d, J=6.3 Hz, 1H), 8.19 (d, J=3.5 Hz, 1H), 7.08 (s, 1H), 4.56 (t,J=13.8 Hz, 2H), 3.84 (s, 2H), 1.21 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.35, −115.25, −187.82.

Example 220:5-(3-chloro-7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneES/MS m/z: 397.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57-11.45 (m, 2H),8.39 (d, J=6.4 Hz, 1H), 8.19 (s, 1H), 7.19 (s, 1H), 4.56 (t, J=13.7 Hz,2H), 3.85 (s, 2H), 1.22 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.85,−115.25.

Example 221.5-(7-(3,3-difluoro-4-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-difluoro-4-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine(240 mg, 0.638 mmol, 1 equiv) in MeOH (3.0 mL) was added 1 N HCl (3.0mL). The solution was heated to 80° C. and stirred for 5 h prior topurification by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) toafford the title compound as the TFA salt. ES/MS m/z: 349.1 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 11.58 (s, 1H), 8.42 (d, J=6.1Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 6.97 (s, 1H), 6.44 (d, J=2.3 Hz, 1H),4.63-4.51 (m, 2H), 4.37-4.30 (m, 1H), 3.71-3.63 (m, 1H), 2.97-2.79 (m,1H), 1.16 (d, J=6.8 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.07,−109.83 (d, J=226.5 Hz), −113.68 (d, J=227.8 Hz).

Example 222.5-(7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoropyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneas the TFA salt was prepared in the manner described for Example 1, butreplacing7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewith7-(3,3-difluoro-4-methylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-3-fluoropyrazolo[1,5-a]pyrimidine.The solution was heated to 80° C. and stirred for 2 h and 20 min priorto purification. ES/MS m/z: 367.0 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.57-11.42 (m, 2H), 8.35 (d, J=6.3 Hz, 1H), 8.19 (d, J=3.5 Hz, 1H),7.09 (s, 1H), 4.59-4.44 (m, 2H), 4.28-4.17 (m, 1H), 3.62-3.52 (m, 1H),2.93-2.75 (m, 1H), 1.15 (d, J=6.8 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.30, −109.72 (d, J=227.4 Hz), −113.69 (d, J=227.5 Hz), −187.84.

Example 223.5-(8-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (67mg, 0.217 mmol, 1 equiv) and (3aR,6aS)-octahydrocyclopenta[c]pyrrole (41mg, 0.369 mmol, 1.7 equiv) in ACN (2.0 mL) was added DIPEA (0.08 mL,0.435 mmol, 2 equiv). The reaction mixture was heated to 130° C. andstirred for 5 h. The crude material was purified by RP-HPLC (10-90%MeCN/H₂O with TFA, Gemini-NX column) to afford the title compound as theTFA salt. ES/MS m/z: 339.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.44-11.32 (m, 2H), 8.06 (s, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.61 (s, 1H),6.65 (s, 1H), 4.10-3.95 (m, 2H), 3.77-3.55 (m, 2H), 2.83-2.74 (m, 2H),1.90-1.46 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.27.

Example 224.5-(8-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (64mg, 0.208 mmol, 1 equiv) and 6,6-difluoro-3-azabicyclo[3.1.0]hexanehydrochloride (39 mg, 0.249 mmol, 1.2 equiv) in ACN (2.0 mL) was addedDIPEA (0.09 mL, 0.499 mmol, 2.4 equiv). The reaction mixture was stirredat 95° C. for 2 h, then at 120° C. overnight. The solution was stirredfor an additional 5 h at 140° C. prior to purification by RP-HPLC(10-90% MeCN/H₂O with TFA, Gemini-NX column) to afford the titlecompound as the TFA salt. ES/MS m/z: 347.0 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.44-11.31 (m, 2H), 8.04 (s, 1H), 7.92 (d, J=6.1 Hz, 1H),7.55 (s, 1H), 6.55 (s, 1H), 4.56-3.91 (m, 4H), 2.81-2.72 (m, 2H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −75.29, −129.84 (d, J=157.9 Hz), −155.12 (d,J=158.0 Hz).

Example 225.5-(8-(3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.162 mmol, 1 equiv) and 3-azabicyclo[3.1.0]hexane hydrochloride (21mg, 0.179 mmol, 1.1 equiv) in ACN (2.0 mL) was added DIPEA (0.07 mL,0.389 mmol, 2.4 equiv). The reaction mixture was stirred at 120° C. for3 days, then at 135° C. overnight. The crude material was purified byRP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) twice to afford thetitle compound as the TFA salt. ES/MS m/z: 311.1 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.17 (s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.79 (d, J=1.8 Hz,1H), 7.10 (s, 1H), 4.15-4.06 (m, 2H), 3.91-3.84 (m, 2H), 1.91-1.84 (m,2H), 0.98-0.87 (m, 1H), 0.36-0.28 (m, 1H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.78.

Example 226.5-(8-(cyclopentylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(cyclopentylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.162 mmol, 1 equiv) and cyclopentanamine (0.02 mL, 0.179 mmol, 1.1equiv) in ACN (2.0 mL) was added DIPEA (0.07 mL, 0.389 mmol, 2.4 equiv).The reaction mixture was stirred at 120° C. for 3 days, then at 135° C.overnight. NMP (2.0 mL) was added and the reaction was stirred again at135° C. overnight prior to purification by RP-HPLC (10-90% MeCN/H₂O withTFA, Gemini-NX column) to afford the title compound as the TFA salt.ES/MS m/z: 313.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.51-11.43 (m, 2H),8.19 (d, J=1.6 Hz, 1H), 8.00 (d, J=6.1 Hz, 1H), 7.84 (s, 1H), 7.33 (d,J=6.6 Hz, 1H), 7.02 (s, 1H), 4.05-3.94 (m, 1H), 2.10-1.98 (m, 2H),1.78-1.58 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.80.

Example 227.5-(8-((3,3-difluorocyclopentyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3,3-difluorocyclopentyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.162 mmol, 1 equiv) and 3,3-difluorocyclopentan-1-aminehydrochloride (28 mg, 0.179 mmol, 1.1 equiv) in ACN (2.0 mL) was addedDIPEA (0.07 mL, 0.389 mmol, 2.4 equiv). The reaction mixture was stirredat 120° C. for 3 days, then at 135° C. overnight. NMP (2.0 mL) was addedand the reaction was stirred again at 135° C. overnight. Additional3,3-difluorocyclopentan-1-amine hydrochloride (28 mg, mmol, 1.1 equiv)and DIPEA (0.07 mL, 0.389 mmol, 2.4 equiv) were added and the reactionwas stirred at 150° C. overnight prior to purification by RP-HPLC(10-90% MeCN/H₂O with TFA, Gemini-NX column) to afford the titlecompound as the TFA salt. ES/MS m/z: 349.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.50-11.38 (m, 2H), 8.14 (s, 1H), 7.97 (d, J=5.8 Hz, 1H),7.74 (s, 1H), 7.59 (d, J=7.0 Hz, 1H), 6.90 (s, 1H), 4.30-4.23 (m, 1H),2.73-2.59 (m, 1H), 2.37-2.09 (m, 4H), 2.00-1.85 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −74.99, −88.82.

Example 228.5-(8-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.162 mmol, 1 equiv) and 6,6-dimethyl-3-azabicyclo[3.1.0]hexanehydrochloride (56 mg, 0.379 mmol, 2.34 equiv) in NMP (2.0 mL) was addedDIPEA (0.07 mL, 0.389 mmol, 2.4 equiv). The solution was heated to 130°C. and stirred overnight. The crude material was purified by RP-HPLC(10-90% MeCN/H₂O with TFA, Gemini-NX column) to afford the titlecompound as the TFA salt. ES/MS m/z: 339.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.40-11.32 (m, 2H), 8.03 (d, J=1.2 Hz, 1H), 7.93 (d, J=6.1Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 6.54 (s, 1H), 4.91-3.47 (m, 4H),1.63-1.59 (m, 2H), 1.07 (s, 3H), 0.86 (s, 3H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.23.

Example 229.(S)-5-(8-(3-(difluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(5)-5-(8-(3-(difluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.162 mmol, 1 equiv), (S)-3-(difluoromethyl)pyrrolidinehydrochloride (28 mg, 0.179 mmol, 1.1 equiv) and DIPEA (0.07 mL, 0.389mmol, 2.4 equiv) in NMP (2.0 mL) was heated to 130° C. and stirredovernight. The crude material was purified by RP-HPLC (10-90% MeCN/H₂Owith TFA, Gemini-NX column) twice to afford the title compound as theTFA salt. ES/MS m/z: 349.1 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.15(s, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.00 (s, 1H),6.22-5.87 (m, 1H), 4.14-3.85 (m, 4H), 3.02-2.88 (m, 1H), 2.36-2.26 (m,1H), 2.24-2.11 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.70,−121.85-−124.29 (m).

Example 230.(R)-5-(8-(3-(difluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3-(difluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.162 mmol, 1 equiv), (R)-3-(difluoromethyl)pyrrolidinehydrochloride (28 mg, 0.179 mmol, 1.1 equiv) and potassium carbonate (65mg, 0.470 mmol, 2.9 equiv) in EtOH (2.0 mL) was heated to 85° C. andstirred for 3 days. The reaction mixture was then heated to 120° C. andstirred overnight. The solution was diluted with water and extractedwith EtOAc (5×). The organic layers were combined, dried over Na₂SO₄,filtered and concentrated in vacuo prior to purification by RP-HPLC(10-90% MeCN/H₂O with TFA, Gemini-NX column) to afford the titlecompound as the TFA salt. ES/MS m/z: 349.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.42-11.33 (m, 2H), 8.03 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 6.61 (s, 1H), 6.38-6.05 (m, 1H),4.19-3.54 (m, 4H), 2.99-2.82 (m, 1H), 2.24-2.12 (m, 1H), 2.09-1.96 (m,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.14, −120.45-−120.63 (m).

Example 231.4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)benzonitrile

4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)benzonitrilewas prepared as follows: To a solution of4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)benzonitrile(32 mg, 0.066 mmol, 1 equiv) in MeOH (0.5 mL) was added 1 N HCl (0.5mL). The solution was heated to 70° C. and stirred. Upon completion, thereaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini-NX column) to afford the title compound as the TFA salt. ES/MSm/z: 452.0 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.33 (m, 2H), 8.08(d, J=1.2 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.88-7.82 (m, 2H), 7.57 (d,J=1.2 Hz, 1H), 7.33-7.28 (m, 2H), 6.63 (s, 1H), 5.68-5.56 (m, 1H),4.71-4.06 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.16, −106.94 (d,J=242.9 Hz), −120.26 (d, J=238.8 Hz).

Example 232.5-(8-(4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of8-(4-((5-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-(6.9mg, 0.014 mmol, 1 equiv) in MeOH (0.5 mL) was added 1 N HCl (0.5 mL).The solution was heated to 70° C. and stirred. Upon completion, thereaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini-NX column) to afford the title compound as the TFA salt. ES/MSm/z: 478.0 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.40-8.37 (m, 1H),8.12 (s, 1H), 8.02 (d, J=1.5 Hz, 1H), 7.93 (dd, J=8.7, 2.4 Hz, 1H), 7.66(d, J=1.5 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.99-6.69 (m, 2H), 6.04-5.97(m, 1H), 4.62-4.39 (m, 3H), 4.27-4.19 (m, 1H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.92, −109.78 (d, J=242.6 Hz), −112.51, −123.83 (d,J=242.6 Hz).

Example 233.1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluorophenyl)carbamate

1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluorophenyl)carbamate was prepared as follows: To a solution of1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluorophenyl)carbamate (66 mg, 0.128 mmol, 1 equiv) in MeOH (2.0 mL)was added 1 N HCl (2.0 mL). The solution was heated to 70° C. andstirred. Upon completion, the reaction mixture was purified by RP-HPLC(10-90% MeCN/H₂O with TFA, Gemini-NX column) to afford the titlecompound as the TFA salt. ES/MS m/z: 488.0 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.46-11.35 (m, 2H), 9.79 (s, 1H), 8.11-8.07 (m, 1H),7.97-7.91 (m, 1H), 7.67-7.56 (m, 2H), 7.29-7.13 (m, 3H), 6.67-6.62 (m,1H), 5.62-5.53 (m, 1H), 4.60-4.14 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.32-−75.49 (m), −107.37-−108.88 (m), −120.37 (d, J=239.0 Hz),−124.64.

Example 234.3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2-fluorophenyl)carbamate

3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2-fluorophenyl)carbamate was prepared as follows: To a solution of3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2-fluorophenyl)carbamate (16 mg, 0.028 mmol, 1 equiv) in ACN (2.0 mL)was added TFA (0.04 mL, 0.550 mmol, 20 equiv). The solution was stirredat room temperature for 15 min prior to purification by RP-HPLC (10-90%MeCN/H₂O with TFA, Gemini-NX column) to afford the title compound as theTFA salt. ES/MS m/z: 477.0 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.58-11.52 (m, 2H), 9.70 (s, 1H), 8.29 (s, 1H), 8.03 (d, J=6.4 Hz, 1H),7.75 (s, 1H), 7.64-7.54 (m, 1H), 7.42 (s, 1H), 7.27-7.13 (m, 3H), 4.90(t, J=12.8 Hz, 2H), 4.66 (t, J=13.8 Hz, 2H).

Example 235.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4-difluorophenyl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4-difluorophenyl)carbamate was prepared as follows: To a solution of(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4-difluorophenyl)carbamate (23 mg, 0.037 mmol, 1 equiv) in ACN (1.0mL) was added TFA (0.1 mL, 0.0015 mmol, 40 equiv). The solution wasstirred at room temperature. Upon completion, the crude material waspurified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) toafford the title compound as the TFA salt. ES/MS m/z: 506.0 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.45-11.36 (m, 2H), 9.79 (s, 1H), 8.09 (s,1H), 7.94 (d, J=6.1 Hz, 1H), 7.66-7.54 (m, 2H), 7.31 (ddd, J=11.2, 9.0,2.9 Hz, 1H), 7.12-7.04 (m, 1H), 6.63 (s, 1H), 5.61-5.51 (m, 1H),4.63-3.60 (m, 4H).

Example 236.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluoro-4-methylphenyl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluoro-4-methylphenyl)carbamate as the TFA salt was prepared in themanner described for Example 235, but replacing(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4-difluorophenyl)carbamate with(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluoro-4-methylphenyl)carbamate. ES/MS m/z: 502.0 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.44-11.36 (m, 2H), 9.65 (s, 1H), 8.09 (d, J=1.2 Hz,1H), 7.94 (d, J=6.1 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.50-7.39 (m, 1H),7.10-7.03 (m, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.63 (s, 1H), 5.60-5.51 (m,1H), 4.60-3.51 (m, 4H), 2.28 (s, 3H).

Example 237.(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)benzonitrile

(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)benzonitrileas the TFA salt was separated from Example 231 by SFC AD-H column(co-solvent: 40% EtOH). ES/MS m/z: 452.0 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.43-11.35 (m, 2H), 8.07 (d, J=1.2 Hz, 1H), 7.93 (d, J=5.2Hz, 1H), 7.88-7.82 (m, 2H), 7.57 (d, J=1.2 Hz, 1H), 7.33-7.27 (m, 2H),6.62 (s, 1H), 5.67-5.56 (m, 1H), 4.63-4.13 (m, 4H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −73.96, −106.93 (d, J=240.7 Hz), —120.26 (d, J=238.7 Hz).

Example 238.3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,4-difluorophenyl)carbamate

3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,4-difluorophenyl)carbamate as the TFA salt was prepared in the mannerdescribed for Example 234, but replacing3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2-fluorophenyl)carbamate with3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,4-difluorophenyl)carbamate. ES/MS m/z: 495.0 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.58-11.46 (m, 2H), 9.71 (s, 1H), 8.23 (s, 1H), 8.02 (d,J=5.8 Hz, 1H), 7.67 (s, 1H), 7.63-7.51 (m, 1H), 7.39-7.24 (m, 2H),7.14-7.02 (m, 1H), 4.88 (t, J=13.1 Hz, 2H), 4.64 (t, J=14.0 Hz, 2H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −74.04, −113.53, −115.01, −119.65.

Example 239.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4,6-trifluorophenyl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4,6-trifluorophenyl)carbamate as the TFA salt was prepared in themanner described for Example 235, but replacing(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4-difluorophenyl)carbamate with(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,4,6-trifluorophenyl)carbamate. ES/MS m/z: 524.0 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.46-11.35 (m, 2H), 9.69 (s, 1H), 8.09 (d, J=1.2 Hz,1H), 7.94 (d, J=6.1 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.36-7.24 (m, 2H),6.63 (s, 1H), 5.61-5.50 (m, 1H), 4.59-4.08 (m, 4H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.35, −108.09 (d, J=247.5 Hz), −109.72, −116.20, −119.87(d, J=241.9 Hz).

Example 240.(R)-5-(8-(3-(4-fluorophenoxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3-(4-fluorophenoxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (70mg, 0.227 mmol, 1 equiv), (R)-3-(4-fluorophenoxy)pyrrolidine (45 mg,0.250 mmol, 1.1 equiv) and DIPEA (0.08 mL, 0.454 mmol, 2 equiv) in NMP(2.0 mL) was stirred at 110° C. for 6 h. The crude material was purifiedby RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) to afford thetitle compound as the TFA salt. ES/MS m/z: 409.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.41-11.31 (m, 2H), 8.03 (s, 1H), 7.93 (d, J=6.0 Hz, 1H),7.55 (s, 1H), 7.18-7.10 (m, 2H), 7.05-6.98 (m, 2H), 6.60 (s, 1H),5.22-5.14 (m, 1H), 4.26-3.64 (m, 4H), 2.36-2.19 (m, 2H). ¹⁹F NMR (376MHz, DMSO-d6) δ −75.21, −123.95.

Example 241.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluorophenyl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2-fluorophenyl)carbamate as the TFA salt was separated from Example 233by SFC CCO-F2 column (co-solvent: 45% EtOH) and was further purified byRP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column). ES/MS m/z: 488.0[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.46-11.36 (m, 2H), 9.79 (s, 1H),8.09 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.69-7.55 (m, 2H),7.30-7.13 (m, 3H), 6.64 (s, 1H), 5.61-5.53 (m, 1H), 4.58-4.15 (m, 4H).¹⁹F NMR (376 MHz, DMSO-d6) δ −75.21, −107.21-−109.15 (m), —120.37 (d,J=239.0 Hz), −124.63.

Example 242.5-(8-(3-phenoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (23 mg,0.075 mmol, 1 equiv), 3-phenoxypyrrolidine hydrochloride (45 mg, 0.23mmol, 3 equiv), and N,N-diisopropylethylamine (0.013 mL, 0.075 mmol, 1equiv) in N-methyl-2-pyrrolidone (0.5 mL) was heated to 65° C. After 1h, the reaction mixture was allowed to cool to rt and was purified byprep-HPLC (10-90% MeCN/H₂O with TFA modifier) to afford5-(8-(3-phenoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas an off-white solid (TFA Salt). ES/MS m/z: 391.1 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.47-11.23 (m, 2H), 8.03 (s, 1H), 7.93 (d, J=6.1 Hz,1H), 7.55 (s, 1H), 7.39-7.23 (m, 2H), 7.05-6.89 (m, 3H), 6.60 (s, 1H),5.23 (s, 1H), 4.28-3.70 (m, 4H), 2.39-2.18 (m, 2H). ¹⁹F NMR (400 MHz,DMSO-d6) δ −75.10.

Example 243.5-(8-(3-hydroxy-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneBJ3634

Step 1: A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (58 mg,0.19 mmol, 1 equiv), 3-hydroxy-3-methylpyrrolidine hydrochloride (21 mg,0.21 mmol, 1.1 equiv), and N,N-diisopropylethylamine (0.033 mL, 0.19mmol, 1 equiv) in N-methyl-2-pyrrolidone (0.5 mL) was heated to 100° C.After 1 h, the reaction mixture was allowed to cool to rt and waspurified by prep-HPLC (10-90% MeCN/H₂O with TFA modifier) to afford5-(8-(3-hydroxy-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas an off-white solid (TFA Salt). ES/MS m/z: 329.1 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.40-11.27 (m, 2H), 8.01 (s, 1H), 7.93 (d, J=6.1 Hz,1H), 7.54 (s, 1H), 6.54 (s, 1H), 4.14-3.46 (m, 4H), 2.03-1.86 (m, 2H),1.39 (s, 3H). ¹⁹F NMR (400 MHz, DMSO-d6) δ −74.89.

Example 244.5-(7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneBJ3631

Step 1: A solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (100 mg,0.53 mmol, 1 equiv), 3-fluoro-3-(trifluoromethyl)azetidine;hydrochloride (105 mg, 0.59 mmol, 1.1 equiv), DIPEA (0.095 mL, 0.53mmol, 1 equiv), and MeCN (1 mL) was heated to 85° C. After 1 h, thereaction mixture was filtered, concentrated and directly purified bySiO₂ chromatography (0-20% MeOH/DCM), affording5-chloro-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 295.1 [M+H].

Step 2: A solution of5-chloro-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)pyrazolo[1,5-a]pyrimidine(15 mg, 0.05 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(11 mg, 0.06 mmol, 1.2 equiv), cesium carbonate (50 mg, 0.15 mmol, 3equiv), and PdCl₂(dppf)-CH₂Cl₂ (4 mg, 0.005 mmol, 0.1 equiv) in 1:4water/1,4-dioxane (2.5 mL) was heated to 90° C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording5-(2,4-dimethoxypyrimidin-5-yl)-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 399.1 [M+H].

Step 3: A solution of5-(2,4-dimethoxypyrimidin-5-yl)-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)pyrazolo[1,5-a]pyrimidine(10 mg, 0.025 mmol, 1 equiv) in 1:1 1N HCl:MeOH (0.5 mL) was heated to80° C. After 6 h, the reaction mixture was allowed to cool to rt and waspurified by prep-HPLC (10-90% MeCN/H₂O with TFA modifier) to afford5-(7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneas an white solid (TFA Salt). ES/MS m/z: 371.00 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.44 (s, 2H), 8.33 (d, J=6.3 Hz, 1H), 8.07 (d, J=2.3 Hz,1H), 7.04 (s, 1H), 6.53 (s, 1H), 6.40 (d, J=2.3 Hz, 1H), 5.01-4.82 (m,4H). ¹⁹F NMR (400 MHz, DMSO-d6) δ −73.95, −82.72.

Example 245.N-(1-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl)acetamideBJ3633

Step 1: A solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (100 mg,0.53 mmol, 1 equiv), N-pyrrolidin-3-ylacetamide (75 mg, 0.59 mmol, 1.1equiv), DIPEA (0.095 mL, 0.53 mmol, 1 equiv), and MeCN (1 mL) was heatedto 85° C. After 1 h, the reaction mixture was filtered, concentrated anddirectly purified by SiO₂ chromatography (0-20% MeOH/DCM), affordingN-(1-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl)acetamide.ES/MS m/z: 280.1 [M+H].

Step 2: A solution ofN-(1-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl)acetamide(120 mg, 0.43 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(95 mg, 0.51 mol, 1.2 equiv), cesium carbonate (500 mg, 1.29 mmol, 3equiv), and PdCl₂(dppf)-CH₂Cl₂ (35 mg, 0.18 mmol, 0.1 equiv) in 1:4water/1,4-dioxane (2.5 mL) was heated to 90° C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affordingN-(1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl)acetamide.ES/MS m/z: 384.1 [M+H].

Step 3: A solution ofN-(1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl)acetamide(69 mg, 0.18 mmol, 1 equiv) in 1:1 1N HCl:MeOH (0.5 mL) was heated to80° C. After 6 h, the reaction mixture was allowed to cool to rt and waspurified by prep-HPLC (10-90% MeCN/H₂O with TFA modifier) to affordN-(1-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-yl)acetamideas an white solid (TFA Salt). ES/MS m/z: 356.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.98-11.41 (m, 2H), 8.46 (d, J=6.1 Hz, 1H), 8.23 (d, J=6.4Hz, 1H), 8.10 (s, 1H), 6.87 (s, 1H), 6.43 (s, 1H), 4.45-3.81 (m, 5H),2.30-2.12 (m, 1H), 2.05-1.88 (m, 1H)), 1.83 (s, 3H). ¹⁹F NMR (400 MHz,DMSO-d6) δ −74.71.

Example 246.5-(7-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneBJ3630

Step 1: A solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine (100 mg,0.53 mmol, 1 equiv), 3-Hydroxy-3-methylpyrrolidine hydrochloride (59 mg,0.59 mmol, 1.1 equiv), DIPEA (0.095 mL, 0.53 mmol, 1 equiv), and MeCN (1mL) was heated to 85° C. After 1 h, the reaction mixture was filtered,concentrated and directly purified by SiO₂ chromatography (0-20%MeOH/DCM), affording1-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3-methylpyrrolidin-3-ol. ES/MSm/z: 254.1 [M+H].

Step 2: A solution of1-(5-chloropyrazolo[1,5-a]pyrimidin-7-yl)-3-methyl-pyrrolidin-3-ol (100mg, 0.47 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (105mg, 0.57 mol, 1.2 equiv), cesium carbonate (464 mg, 1.42 mmol, 3 equiv),and PdCl₂(dppf)-CH₂Cl₂ (38 mg, 0.05 mmol, 0.1 equiv) in 1:4water/1,4-dioxane (2.5 mL) was heated to 90° C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording1-[5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol.ES/MS m/z: 357.1 [M+H].

Step 3: A solution of1-[5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl]-3-methyl-pyrrolidin-3-ol(68 mg, 0.19 mmol, 1 equiv) in 1:1 1N HCl:MeOH (0.5 mL) was heated to80° C. After 6 h, the reaction mixture was allowed to cool to rt and waspurified by prep-HPLC (10-90% MeCN/H₂O with TFA modifier) to afford5-(7-(3-hydroxy-3-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dioneas an white solid (TFA Salt). ES/MS m/z: 329.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 12.03-11.45 (m, 2H), 8.46 (d, J=5.9 Hz, 1H), 8.10 (s, 1H),6.81 (s, 1H), 6.44 (s, 1H), 4.62-3.07 (m, 4H), 2.07-1.86 (m, 2H), 1.40(s, 3H). ¹⁹F NMR (400 MHz, DMSO-d6) δ −74.63.

Example 247.4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzonitrile

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (54mg, 0.18 mmol, 1 equiv), 4-(azetidin-3-yl)benzonitrile (31 mg, 0.19mmol, 1.1 equiv), and DIPEA (0.05 mL, 0.26 mmol, 1.5 equiv) werecombined in NMP (0.5 mL) and stirred at 120° C. for 4 hours. The mixturewas cooled, diluted with water, TFA, and MeCN, and purified by RP-HPLC(10-80% MeCN/H₂O with TFA modifier) affording4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzonitrileas a TFA salt. ES/MS m/z: 386.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.51-11.22 (m, 2H), 8.03 (d, J=1.2 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H),7.89-7.81 (m, 2H), 7.73-7.60 (m, 2H), 7.55 (d, J=1.2 Hz, 1H), 6.50 (s,1H), 4.81 (s, 2H), 4.37 (s, 2H), 4.25-4.15 (m, 1H).

Example 248.5-(8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with3-(4-(trifluoromethyl)phenyl)pyrrolidine. ES/MS m/z: 443.2 [M+H]. ¹H NMR(400 MHz, DMSO-d6) δ 11.37 (d, J=2.0 Hz, 1H), 11.34 (d, J=6.2 Hz, 1H),8.01 (d, J=1.1 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H),7.61 (d, J=8.1 Hz, 2H), 7.53 (s, 1H), 6.61 (s, 1H), 4.35-3.74 (m, 2H),3.75-3.40 (m, 3H), 2.43 (s, 1H), 2.17 (p, J=9.4 Hz, 1H).

Example 249.5-(8-(3-(3-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(3-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with3-(3-(trifluoromethyl)phenyl)pyrrolidine. ES/MS m/z: 443.2 [M+H]. ¹H NMR(400 MHz, Methanol-d4) δ 8.09 (s, 1H), 7.95 (d, J=1.4 Hz, 1H), 7.71 (s,1H), 7.67 (d, J=6.9 Hz, 1H), 7.62-7.52 (m, 3H), 6.81 (s, 1H), 4.51 (s,1H), 4.15 (s, 1H), 3.95 (s, 2H), 3.83-3.61 (m, 1H), 2.67-2.44 (m, 1H),2.27 (q, J=10.2 Hz, 1H).

Example 250.5-(8-(3-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with3-(2-(trifluoromethyl)phenyl)pyrrolidine. ES/MS m/z: 443.2 [M+H]. ¹H NMR(400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.14 (d, J=1.8 Hz, 1H), 7.79 (d,J=1.9 Hz, 1H), 7.77-7.71 (m, 2H), 7.67 (t, J=7.6 Hz, 1H), 7.47 (t, J=7.6Hz, 1H), 7.16 (s, 1H), 4.34 (s, 1H), 4.15 (t, J=9.0 Hz, 1H), 4.01 (h,J=9.4, 8.9 Hz, 3H), 2.53 (d, J=5.5 Hz, 1H), 2.37 (t, J=10.8 Hz, 1H).

Example 251.5-(8-(3-(4-methoxyphenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(4-methoxyphenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with 3-(4-methoxyphenyl)azetidine. ES/MSm/z: 391.1 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 8.07 (s,1H), 7.74 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.7 Hz, 2H), 6.88(s, 1H), 4.91-4.87 (m, 2H), 4.45 (t, J=7.7 Hz, 2H), 4.12 (q, J=7.1, 6.5Hz, 1H), 3.79 (s, 3H).

Example 252.5-(8-(3-(4-(trifluoromethoxy)phenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(4-(trifluoromethoxy)phenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with3-(4-(trifluoromethoxy)phenyl)azetidine. ES/MS m/z: 445.1 [M+H]. ¹H NMR(400 MHz, Methanol-d4) δ 8.10 (s, 1H), 7.99 (d, J=1.4 Hz, 1H), 7.64 (s,1H), 7.57 (d, J=8.6 Hz, 2H), 7.33-7.23 (m, 2H), 6.75 (s, 1H), 4.90 (d,J=9.0 Hz, 2H), 4.46 (d, J=8.1 Hz, 2H), 4.24-4.09 (m, 1H).

Example 253.5-(8-(3-fluoro-3-phenylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-phenylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with 3-fluoro-3-phenylpyrrolidine. ES/MSm/z: 392.9 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.28 (m, 2H), 8.04(d, J=1.1 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.61 (d, J=7.2 Hz, 2H), 7.55(d, J=1.1 Hz, 1H), 7.51-7.40 (m, 3H), 6.64 (s, 1H), −3.49 (m, 4H),2.81-2.54 (m, 2H).

Example 254.5-(8-(2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-azabicyclo[3.1.0]hexan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with 2-azabicyclo[3.1.0]hexane. ES/MS m/z:311.1 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 8.15 (d,J=1.8 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.33 (s, 1H), 4.26 (td, J=10.6,3.8 Hz, 1H), 3.95 (d, J=6.7 Hz, 1H), 3.52-3.37 (m, 1H), 2.54-2.38 (m,1H), 2.21 (ddd, J=12.7, 8.6, 3.8 Hz, 1H), 1.96 (dt, J=14.9, 6.2 Hz, 1H),1.09 (dt, J=8.7, Hz, 1H), 0.74 (td, J=5.4, 2.5 Hz, 1H).

Example 255.5-(8-(3-fluoro-3-(4-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-(4-fluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with3-fluoro-3-(4-fluorophenyl)pyrrolidine. ES/MS m/z: 410.9 [M+H]. ¹H NMR(400 MHz, Methanol-d4) δ 8.06 (s, 1H), 7.90 (d, J=1.3 Hz, 1H), 7.64 (dd,J=8.6, 5.2 Hz, 2H), 7.51 (d, J=1.3 Hz, 1H), 7.19 (t, J=8.7 Hz, 2H), 6.70(s, 1H), 4.77-4.51 (m, 1H), 4.29 (dd, J=36.5, 13.1 Hz, 2H), 4.04 (s,1H), 2.81-2.50 (m, 2H).

Example 256.5-(8-(3-fluoro-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with3-fluoro-3-(4-(trifluoromethyl)phenyl)pyrrolidine. ES/MS m/z: 461.1[M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 8.17 (d, J=1.8 Hz,1H), 7.85 (s, 1H), 7.82 (q, J=8.6, 7.3 Hz, 4H), 7.23 (s, 1H), 4.65-4.32(m, 2H), 4.31-4.07 (m, 2H), 2.93-2.60 (m, 2H).

Example 257.5-(8-(2-azabicyclo[3.2.0]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-azabicyclo[3.2.0]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 247, but replacing4-(azetidin-3-yl)benzonitrile with 2-azabicyclo[3.2.0]heptane. ES/MSm/z: 325.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 2H), 7.98 (d,J=1.1 Hz, 1H), 7.93 (s, 1H), 7.51 (d, J=1.1 Hz, 1H), 6.57 (s, 1H),4.23-3.49 (m, 2H), 3.32 (s, 1H), 3.18 (h, J=6.4, 6.0 Hz, 1H), 2.36 (dq,J=11.7, 6.6, 5.8 Hz, 1H), 2.09 (d, J=10.8 Hz, 1H), 2.05-1.95 (m, 1H),1.93-1.82 (m, 1H), 1.71 (d, J=14.7 Hz, 2H).

Example 258.5-(8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(4-fluorophenyl)azetidin-1-yl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS m/z: 379.1 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.13 (s, 1H), 8.04 (s, 1H), 7.70 (s, 1H),7.54-7.41 (m, 2H), 7.18-7.05 (m, 2H), 6.82 (s, 1H), 4.89 (d, J=9.3 Hz,2H), 4.46 (t, J=7.5 Hz, 2H), 4.22-4.07 (m, 1H).

Example 259.5-(8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-phenylazetidin-1-yl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS m/z: 379.1 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.29-8.13 (m, 2H), 7.91 (d, J=1.8 Hz, 1H),7.62 (d, J=7.9 Hz, 2H), 7.47 (dt, J=23.4, 7.2 Hz, 3H), 7.18 (s, 1H),4.96 (s, 2H), 4.90 (s, 2H).

Example 260.5-(8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(4,4-difluoro-6-azaspiro[2.5]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS m/z: 375.1 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.26 (d, J=2.5 Hz, 2H), 7.96 (d, J=1.9 Hz,1H), 7.76 (s, 1H), 4.06 (t, J=10.8 Hz, 2H), 3.88-3.71 (m, 2H), 1.97-1.85(m, 2H), 1.07-0.89 (m, 2H), 0.72-0.50 (m, 2H).

Example 261. Methyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate

Methyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl4-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoateand isolated by filtration as an HCl salt. ES/MS m/z: 419.1 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.10 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.98(s, 1H), 7.62 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 6.72 (s, 1H), 4.94-4.87(m, 2H), 4.56-4.42 (m, 2H), 4.22 (d, J=7.9 Hz, 1H), 3.91 (s, 3H).

Example 262.5-(3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-(3-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS m/z: 461.1 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 7.68 (d, J=8.1 Hz, 2H),7.63-7.56 (m, 3H), 7.12 (s, 1H), 4.43 (s, 1H), 4.12 (s, 1H), 3.95 (s,2H), 3.83-3.69 (m, 1H), 2.58 (s, 1H), 2.29 (p, J=9.7 Hz, 1H).

Example 263. Methyl3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate

Methyl3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl3-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoateand isolated by filtration as an HCl salt. ES/MS m/z: 419.1 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.18 (s, 1H), 8.13 (q, J=1.9 Hz, 2H), 7.96(dt, J=7.7, 1.4 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H),7.53 (t, J=7.8 Hz, 1H), 6.98 (s, 1H), 4.92 (q, J=8.3, 7.7 Hz, 2H),4.59-4.46 (m, 2H), 4.26 (ddd, J=14.6, 8.6, 5.9 Hz, 1H), 3.91 (s, 3H).

Example 264. Methyl3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate

Methyl3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoatewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl3-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoateand isolated by filtration as an HCl salt. ES/MS m/z: 433.1 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 8.23 (d, J=2.0 Hz, 1H),8.11-8.05 (m, 1H), 7.96 (dt, J=7.8, 1.4 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H),7.68 (dt, J=7.7, 1.5 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.35 (s, 1H), 4.37(t, J=8.8 Hz, 1H), 4.09 (t, J=9.3 Hz, 1H), 4.03-3.91 (m, 2H), 3.92 (s,3H), 3.84-3.72 (m, 1H), 2.67-2.52 (m, 1H), 2.35 (p, J=10.3 Hz, 1H).

Example 265. Methyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoate

Methyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoatewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith methyl4-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoateand isolated by filtration as an HCl salt. ES/MS m/z: 433.2 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.24 (s, 1H), 8.21 (d, J=2.0 Hz, 1H),8.08-7.99 (m, 2H), 7.89 (d, J=2.0 Hz, 1H), 7.60-7.49 (m, 2H), 7.30 (s,1H), 4.37 (t, J=8.9 Hz, 1H), 4.08 (d, J=5.6 Hz, 1H), 3.98 (dd, J=17.3,9.0 Hz, 2H), 3.91 (s, 3H), 3.77 (td, J=15.6, 14.3, 7.1 Hz, 1H),2.66-2.53 (m, 1H), 2.33 (p, J=10.0 Hz, 1H).

Example 266.5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[4,3-b]pyridazineand isolated by filtration as an HCl salt. ES/MS m/z: 362.1 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.47 (s, 2H), 9.45 (s, 1H), 7.99 (s, 1H), 6.60(s, 1H), 4.56 (s, 2H), 4.09 (q, J=5.2 Hz, 2H), 1.06 (d, J=3.6 Hz, 2H),1.03 (d, J=3.7 Hz, 2H).

Example 267.5-(8-(3-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1. To a suspension of methyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate(240 mg, 0.57 mmol, 1 equiv) in 1:1 MeOH/THF (6 mL) was added 1M lithiumhydroxide (2.9 mL, 2.8 mmol, 5 equiv). The reaction was stirred at roomtemperature for 3 hours, then quenched with 1M HCl (3 mL) andconcentrated, affording4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoicacid. This material was taken forward without further purification.ES/MS m/z: 405.1 [M+H].

Step 2. To a mixture of4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoicacid (30 mg, 0.07 mmol, 1 equiv) in pyridine (1 mL) was added3,3-difluoroazetidine hydrochloride (10.4 mg, 0.08 mmol, 1.1 equiv) andN-Ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (16.8 mg,0.087 mmol, 1.2 equiv). The reaction mixture was stirred for 15 h thenconcentrated. The residue was taken up in acetonitrile and water (2 mL)and purified by RP-HPLC (10-80% MeCN/H₂O with TFA modifier) to provide5-(8-(3-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas the TFA salt. ES/MS m/z: 480.1 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ8.19 (s, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.78-7.69(m, 2H), 7.60 (d, J=8.2 Hz, 2H), 7.01 (s, 1H), 4.92 (t, J=8.9 Hz, 2H),4.77-4.40 (m, 6H), 4.32-4.18 (m, 1H).

Example 268.5-(8-(3-(3-(3,3-difluoroazetidine-1-carbonyl)phenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(3-(3,3-difluoroazetidine-1-carbonyl)phenyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 267, but replacingmethyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewith methyl3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoate.ES/MS m/z: 480.1 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.06 (s, 1H),7.90 (d, J=1.3 Hz, 1H), 7.77 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.63-7.58(m, 1H), 7.55-7.48 (m, 2H), 6.59 (s, 1H), 4.73-4.43 (m, 8H), 4.25-4.10(m, 1H).

Example 269.3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-N-methylbenzamide

3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-N-methylbenzamidewas prepared in the manner described for Example 267, but replacingmethyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewith methyl3-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoatein step 1, and replacing 3,3-difluoroazetidine hydrochloride withmethylamine in step 2. ES/MS m/z: 432.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6)δ 11.34 (s, 2H), 8.45 (d, J=4.8 Hz, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.94(s, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.72 (dt, J=7.6, 1.4 Hz, 1H), 7.57-7.48(m, 2H), 7.43 (t, J=7.6 Hz, 1H), 6.59 (s, 1H), 4.03-3.69 (m, 3H), 3.61(p, J=8.2 Hz, 1H), 2.78 (d, J=4.5 Hz, 3H), 2.47-2.37 (m, 2H), 2.17 (p,J=10.2 Hz, 1H).

Example 270.4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-N-methylbenzamide

4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-N-methylbenzamidewas prepared in the manner described for Example 267, but replacingmethyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)azetidin-3-yl)benzoatewith methyl4-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)benzoatein step 1, and replacing 3,3-difluoroazetidine hydrochloride withmethylamine in step 2. ES/MS m/z: 432.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6)δ 11.36 (s, 1H), 11.33 (d, J=6.0 Hz, 1H), 8.39 (d, J=4.7 Hz, 1H), 7.99(d, J=1.1 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.85-7.75 (m, 2H), 7.50 (d,J=1.2 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 6.58 (s, 1H), 3.82 (s, 3H), 3.62(q, J=8.3 Hz, 1H), 2.78 (d, J=4.5 Hz, 3H), 2.46-2.36 (m, 2H), 2.24-2.07(m, 1H).

Example 271.5-(8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(RACEMIC)

Step 1. To a mixture of((1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)boronicacid (115 mg, 0.48 mmol, 1 equiv), 4-bromo-2-(trifluoromethyl)pyrimidine(176 mg, 0.78 mmol, 1.6 equiv), and potassium phosphate tribasic (308mg, 1.45 mmol, 3 equiv) in 3:1 dioxane/H₂O (2.5 mL) was addedmesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II)(35 mg, 0.05 mmol, 0.1 equiv). The reaction was purged with Argon andstirred at 110° C. for 5 h. The reaction mixture was directly purifiedby silica gel chromatography (0-100% EtOAc/hexanes), affording6-chloro-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 340.1 [M+H].

Step 2. A mixture of6-chloro-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine(10 mg, 0.03 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(6.5 mg, 0.04 mmol, 1.2 equiv), Pd(dppf)Cl₂—CH₂Cl₂ (2.2 mg, 0.003 mmol,0.1 equiv), and cesium carbonate (24 mg, 0.07 mmol, 2.5 equiv) in 3:1dioxane/H₂O (1.2 mL) was purged with Argon and stirred at 80° C. for 1h. The reaction mixture was purified directly by silica gelchromatography (0-100% EtOAc/hexanes), affording6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 444.2 [M+H].

Step 3. To a solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine(3.8 mg, 0.009 mmol, 1 equiv) in MeOH (2.5 mL) was added aqueous 1 M HCl(2.5 mL). The reaction was stirred at 80° C. for 4.5 h. The reaction wasconcentrated and purified by RP-HPLC (10-70% MeCN/H₂O with AcOHmodifier) to afford5-(8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 416.2 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J=5.2Hz, 1H), 8.17 (s, 1H), 8.09 (d, J=1.3 Hz, 1H), 7.70 (d, J=5.2 Hz, 1H),7.66 (d, J=1.3 Hz, 1H), 7.64 (s, 1H), 3.27-3.19 (m, 1H), 3.03-2.91 (m,1H), 2.12 (dd, J=8.2, 6.6 Hz, 2H).

Example 272.5-(8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-70% MeCN/H₂O with TFA modifier). ES/MS m/z:416.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=4.5 Hz, 2H), 9.01(s, 2H), 8.34 (d, J=1.3 Hz, 1H), 8.03 (d, J=6.3 Hz, 1H), 7.86 (s, 1H),7.66 (s, 1H), 3.05 (dt, J=9.2, 5.6 Hz, 1H), 2.97 (ddd, J=8.8, 6.1, 4.4Hz, 1H), 2.36-2.26 (m, 1H), 2.02 (dt, J=8.9, 5.5 Hz, 1H).

Example 273.5-(3-fluoro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1R,2R)-2-(2-(trifluoromethyl)pyrimidin-5-yl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-70% MeCN/H₂O with TFA modifier). ES/MS m/z:434.0 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=3.7 Hz, 2H), 9.02(s, 2H), 8.03 (d, J=6.5 Hz, 1H), 7.59 (s, 1H), 7.56 (d, J=7.1 Hz, 1H),3.12 (ddd, J=9.0, 6.1, 4.5 Hz, 1H), 2.96 (ddd, J=8.9, 6.0, 4.4 Hz, 1H),2.37-2.28 (m, 1H), 2.06-1.95 (m, 1H).

Example 2745-(8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-oxa-7-azaspiro[4.4]nonaneand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 355.17 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.38(s, 1H), 11.35 (d, J=6.1 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J=6.1 Hz, 1H),7.55 (s, 1H), 6.58 (s, 1H), 3.85-3.80 (m, 4H), 3.66-3.57 (m, 4H), 2.02(td, J=7.1, 2.6 Hz, 2H), 1.99-1.86 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.03.

Example 275.5-(8-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(8-oxa-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8-oxa-2-azaspiro[4.5]decaneand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 369.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.45-11.34 (m, 2H), 8.09 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.0 Hz, 1H),7.67 (d, J=1.4 Hz, 1H), 6.66 (s, 1H), 4.05-3.68 (m, 4H), 3.61 (qdd,J=11.4, 6.4, 4.2 Hz, 4H), 1.95 (t, J=7.1 Hz, 2H), 1.66-1.48 (m, 4H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −75.38.

Example 276.5-(8-((1S,2S)-2-(benzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(benzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazoleand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 403.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.60-11.44 (m, 2H), 9.33 (s, 1H), 8.30 (s, 1H), 8.07 (d, J=1.7 Hz, 1H),8.03 (s, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 7.45(dd, J=8.5, 1.8 Hz, 1H), 2.97 (ddd, J=9.3, 6.1, 4.4 Hz, 1H), 2.81 (dt,J=9.0, 5.3 Hz, 1H), 2.15 (dt, J=8.7, 5.4 Hz, 1H), 1.87 (dt, J=8.6, 5.5Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.83.

Example 277.5-(3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineand isolated by filtration as an HCl salt. ES/MS m/z: 446.13 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.52 (s, 2H), 8.02 (s, 1H), 7.53 (d, J=7.1 Hz,1H), 7.47 (s, 1H), 7.42-7.34 (m, 2H), 7.34-7.26 (m, 2H), 2.88 (ddd,J=9.0, 6.2, 4.4 Hz, 1H), 2.70 (ddd, J=8.9, 6.0, 4.5 Hz, 1H), 2.12 (dt,J=8.9, Hz, 1H), 1.76 (ddd, J=8.8, 6.2, 4.8 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −57.40, −155.61 (d, J=7.2 Hz).

Example 278.5-(8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-5λ3-imidazo[1,2-b][1,2]fluorazineand purified by RP-HPLC (5-100% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 444.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.63-11.47 (m, 2H), 8.02 (d, J=6.4 Hz, 1H), 7.54 (d, J=7.1 Hz, 1H),7.47 (s, 1H), 7.35 (d, J=1.8 Hz, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.13 (dd,J=8.4, 1.8 Hz, 1H), 2.89 (ddd, J=9.0, 6.3, 4.4 Hz, 1H), 2.68 (ddd,J=8.9, 5.9, 4.3 Hz, 1H), 2.11 (dt, J=8.9, 5.3 Hz, 1H), 1.76 (ddd, J=8.8,6.1, 4.8 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −49.74, −75.33, −155.61(d, J=7.1 Hz).

Example 279.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrileand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 389.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.62-11.46 (m, 2H), 8.36 (d, J=1.5 Hz, 1H), 8.03 (d, J=6.1 Hz, 1H),7.91 (s, 1H), 7.83 (dd, J=10.2, 1.6 Hz, 1H), 7.71 (dd, J=8.1, 1.6 Hz,1H), 7.66 (s, 1H), 7.49 (t, J=7.9 Hz, 1H), 3.09-2.97 (m, 1H), 2.86 (ddd,J=8.9, 6.1, 4.5 Hz, 1H), 2.17 (dt, J=9.0, 5.4 Hz, 1H), 1.97-1.84 (m,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.27, −117.79-−118.08 (m).

Example 280.5-(8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 448.11 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58(d, J=6.2 Hz, 1H), 11.56 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 8.05 (d, J=6.2Hz, 1H), 7.97 (d, J=1.5 Hz, 1H), 7.68 (s, 1H), 7.43 (t, J=8.6 Hz, 1H),7.38 (dd, J=10.5, 2.5 Hz, 1H), 7.29-7.20 (m, 1H), 2.97-2.86 (m, 1H),2.79 (dt, J=8.9, 5.6 Hz, 1H), 2.07 (dt, J=9.0, 5.4 Hz, 1H), 1.87 (ddd,J=8.7, 6.3, 5.0 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −57.65, −75.32,−115.92 (t, J=9.6 Hz).

Example 281. methyl4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic methyl4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 404.13 [M+H]. ¹H NMR (400 MHz, Acetonitrile-d3) δ9.43 (s, 1H), 9.32 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.16 (d, J=6.4 Hz,1H), 8.01 (s, 1H), 7.98-7.91 (m, 3H), 7.39-7.33 (m, 2H), 3.89 (s, 3H),2.94 (dt, J=8.7, 5.4 Hz, 1H), 2.68 (ddd, J=9.0, 6.7, 4.4 Hz, 1H),1.93-1.86 (m, 2H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −77.13.

Example 282. methyl3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoate

methyl3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic methyl3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoateand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 404.19 [M+H]. ¹H NMR (400 MHz, Acetonitrile-d3) δ9.39 (s, 1H), 9.29 (s, 1H), 8.18 (d, J=1.8 Hz, 1H), 8.15 (d, J=6.5 Hz,1H), 7.99 (s, 1H), 7.95 (d, J=1.9 Hz, 1H), 7.93-7.84 (m, 2H), 7.53 (d,J=7.7 Hz, 1H), 7.48 (t, J=7.6 Hz, 1H), 3.90 (s, 3H), 2.91 (q, J=6.9 Hz,1H), 2.73 (dq, J=7.6, 4.4 Hz, 1H), 1.94-1.87 (m, 2H). ¹⁹F NMR (376 MHz,Acetonitrile-d3) δ −77.19.

Example 283.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzamide

To4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid (0.195 g, 0.47 mmol) in DMF (1 mL) was added HATU (464 mg, 1.2mmol, 2.6 equiv) followed by DIPEA (0.21 ml, 1.2 mmol, 2.5 equiv) andammonia solution (4.8 mL, 0.5 M in THF, 2.4 mmol, 5 equiv). After 4 h,MeOH (5 mL) was added and the volatiles were removed under reducedpressure. To the resulting mixture was added MeOH (1 mL) and 1 M HClaqueous solution (1 mL), and heated to 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column)affording racemic4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzamideas a TFA salt. ES/MS m/z: 389.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.60-11.42 (m, 2H), 8.30 (d, J=1.4 Hz, 1H), 8.01 (d, J=6.3 Hz, 1H),7.92 (s, 1H), 7.86-7.76 (m, 3H), 7.53 (s, 1H), 7.37-7.30 (m, 2H), 7.29(s, 1H), 2.86 (ddd, J=9.3, 6.3, 4.4 Hz, 1H), 2.82-2.73 (m, 1H), 2.11(dt, J=8.9, 5.2 Hz, 1H), 1.81 (dt, J=8.6, 5.2 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −74.84.

Example 284.3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzamide

3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzamideas a racemate was prepared in the manner described for Example 283, butreplacing racemic4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NXcolumn) as a TFA salt. ES/MS m/z: 389.11 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.64-11.51 (m, 2H), 8.41 (d, J=1.5 Hz, 1H), 8.05 (d, J=6.1Hz, 1H), 7.98 (s, 2H), 7.76-7.69 (m, 2H), 7.66 (s, 1H), 7.45-7.33 (m,3H), 2.88-2.77 (m, 2H), 2.03 (dt, J=8.6, 5.3 Hz, 1H), 1.92-1.82 (m, 1H).¹⁹F NMR (376 MHz, DMSO-d6) δ −75.30.

Example 285.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N-methylbenzamide

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N-methylbenzamideas a racemate was prepared in the manner described for Example 283, butreplacing 0.5 M ammonia in THF with 2 M methylamine in THF and purifiedby RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) as a TFA salt.ES/MS m/z: 403.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57-11.45 (m,2H), 8.46-8.32 (m, 1H), 8.26 (s, 1H), 8.00 (d, J=6.0 Hz, 1H), 7.78 (d,J=8.2 Hz, 2H), 7.75 (s, 1H), 7.49 (s, 1H), 7.33 (d, J=8.4 Hz, 2H),2.93-2.83 (m, 1H), 2.81-2.72 (m, 4H), 2.19-2.07 (m, 1H), 1.84-1.73 (m,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.48.

Example 286.3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N-methylbenzamide

3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N-methylbenzamideas a racemate was prepared in the manner described for Example 283, butreplacing racemic4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and 0.5 M ammonia in THF with 2 M methylamine in THF and purifiedby RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) as a TFA salt.ES/MS m/z: 403.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.61-11.44 (m,2H), 8.51-8.40 (m, 1H), 8.35 (s, 1H), 8.03 (d, J=6.3 Hz, 1H), 7.89 (s,1H), 7.70-7.64 (m, 2H), 7.59 (s, 1H), 7.46-7.36 (m, 2H), 2.87 (dt,J=9.5, 5.6 Hz, 1H), 2.82-2.75 (m, 4H), 2.10-2.01 (m, 1H), 1.88-1.79 (m,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.12.

Example 287.3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N,N-dimethylbenzamide

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N,N-dimethylbenzamideas a racemate was prepared in the manner described for Example 283, butreplacing racemic4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and 0.5 M ammonia in THF with 2 M dimethylamine in THF and purifiedby RP-HPLC (5-50% MeCN/H₂O with TFA, Gemini-NX column) as a TFA salt.ES/MS m/z: 417.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62-11.49 (m,2H), 8.37 (s, 1H), 8.04 (d, J=6.1 Hz, 1H), 7.92 (s, 1H), 7.60 (s, 1H),7.43-7.31 (m, 2H), 7.28-7.26 (m, 1H), 7.24 (dt, J=7.2, 1.5 Hz, 1H), 2.98(s, 3H), 2.91 (s, 3H), 2.88-2.81 (m, 1H), 2.81-2.74 (m, 1H), 2.04 (dt,J=10.5, 5.3 Hz, 1H), 1.82 (dt, J=8.5, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.14.

Example 288.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N,N-dimethylbenzamide

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N,N-dimethylbenzamideas a racemate was prepared in the manner described for Example 283, butreplacing 0.5 M ammonia in THF with 2 M dimethylamine in THF andpurified by RP-HPLC (5-50% MeCN/H₂O with TFA, Gemini-NX column) as a TFAsalt. ES/MS m/z: 417.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (d,J=3.9 Hz, 2H), 8.32 (d, J=1.4 Hz, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.85 (s,1H), 7.55 (s, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 2.95(d, J=11.8 Hz, 6H), 2.83 (ddd, J=9.0, 6.2, 4.4 Hz, 1H), 2.80-2.73 (m,1H), 2.08 (dt, J=8.8, 5.2 Hz, 1H), 1.80 (dt, J=8.5, 5.3 Hz, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −74.95.

Example 289.5-(8-((1S,2S)-2-(4-(azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid (20 mg, 0.05 mmol), azetidine hydrochloride (14 mg, 0.15 mmol, 3equiv), HATU (59 mg, 0.15 mmol, 3 equiv) in DMF (1 mL) followed by DIPEA(0.05 mL, 0.26 mmol, 5 equiv) and stirred for 16 h. Purification wasaccomplished by RP-HPLC (5-90% MeCN/H₂O with TFA, Gemini-NX column)affording racemic5-(8-((1S,2S)-2-(4-(azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ES/MS m/z: 429.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.53 (s, 2H), 8.32 (s, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.84 (s, 1H),7.62-7.50 (m, 3H), 7.37-7.25 (m, 2H), 4.30 (t, J=7.6 Hz, 2H), 4.03 (t,J=7.8 Hz, 2H), 2.87-2.81 (m, 1H), 2.81-2.74 (m, 1H), 2.25 (p, J=7.7 Hz,2H), 2.10 (dt, J=8.9, 5.4 Hz, 1H), 1.81 (dt, J=8.3, 5.2 Hz, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.00.

Example 290.5-(8-((1S,2S)-2-(4-(3-methylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3-methylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with 3-methylazetidinebenzenesulfonate and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 443.10 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.53 (s, 2H), 8.31 (s, 1H), 8.02 (d, J=6.4 Hz, 1H),7.83 (s, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.54 (s, 1H), 7.31 (d, J=8.2 Hz,2H), 4.39 (t, J=8.5 Hz, 1H), 4.14 (t, J=9.2 Hz, 1H), 3.86 (t, J=7.0 Hz,1H), 3.62-3.56 (m, 1H), 2.84 (dt, J=9.8, 5.5 Hz, 1H), 2.77 (dt, J=10.0,5.4 Hz, 1H), 2.74-2.64 (m, 1H), 2.10 (dt, J=9.9, 5.4 Hz, 1H), 1.81 (dd,J=9.6, 5.2 Hz, 1H), 1.20 (d, J=6.9 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−74.96.

Example 291.5-(8-((1S,2S)-2-(4-(3-(trifluoromethyl)azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3-(trifluoromethyl)azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with 3-(trifluoromethyl)azetidine andpurified by RP-HPLC (5-90% MeCN/H₂O with TFA, Gemini-NX column) as a TFAsalt. ES/MS m/z: 497.13 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.64-11.47(m, 2H), 8.36 (d, J=1.5 Hz, 1H), 8.04 (d, J=6.0 Hz, 1H), 7.91 (s, 1H),7.62 (d, J=8.3 Hz, 2H), 7.60 (s, 1H), 7.39-7.30 (m, 2H), 4.59-4.49 (m,1H), 4.40-4.33 (m, 1H), 4.28 (d, J=9.8 Hz, 1H), 4.06-3.97 (m, 1H), 3.67(ddt, J=18.2, 9.5, 5.3 Hz, 1H), 2.84 (tq, J=13.5, 5.1 Hz, 2H), 2.10 (dt,J=8.8, 5.3 Hz, 1H), 1.84 (dt, J=8.3, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −72.83 (d, J=9.2 Hz), −75.18.

Example 292.5-(8-((1S,2S)-2-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with 3,3-difluoroazetidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 465.10 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.61-11.41 (m, 2H), 8.30 (s, 1H), 8.02 (d, J=6.4 Hz,1H), 7.82 (s, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.54 (s, 1H), 7.35 (d, J=8.2Hz, 2H), 4.96-4.62 (m, 2H), 4.62-4.34 (m, 2H), 2.91-2.83 (m, 1H),2.83-2.75 (m, 1H), 2.18-2.07 (m, 1H), 1.82 (dt, J=8.7, 5.2 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −74.94, −100.10 (p, J=12.6 Hz).

Example 293.5-(8-((1S,2S)-2-(4-(3,3-dimethylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3,3-dimethylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with 3,3-dimethylazetidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 457.12 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.64-11.41 (m, 2H), 8.33 (d, J=1.4 Hz, 1H), 8.02 (d,J=6.4 Hz, 1H), 7.85 (s, 1H), 7.62-7.56 (m, 2H), 7.56 (s, 1H), 7.35-7.26(m, 2H), 3.98 (s, 2H), 3.72 (s, 2H), 2.84 (dt, J=8.8, 3.7 Hz, 1H),2.81-2.74 (m, 1H), 2.13-2.05 (m, 1H), 1.81 (dt, J=8.4, 5.2 Hz, 1H), 1.24(s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.06.

Example 294.5-(8-((1S,2S)-2-(3-(azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and purified by RP-HPLC (5-90% MeCN/H₂O with TFA, Gemini-NX column)as a TFA salt. ES/MS m/z: 429.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.70-11.46 (m, 2H), 8.41 (d, J=1.6 Hz, 1H), 8.05 (d, J=6.1 Hz, 1H),7.98 (s, 1H), 7.64 (s, 1H), 7.48-7.45 (m, 1H), 7.45-7.42 (m, 1H),7.42-7.36 (m, 2H), 4.29 (t, J=7.7 Hz, 2H), 4.04 (t, J=7.8 Hz, 2H),2.87-2.73 (m, 2H), 2.25 (p, J=7.7 Hz, 2H), 2.01 (dt, J=8.9, 5.4 Hz, 1H),1.82 (dt, J=8.6, 5.4 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.27.

Example 295.5-(8-((1S,2S)-2-(3-(3-methylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(3-methylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3-methylazetidine benzenesulfonateand purified by RP-HPLC (5-90% MeCN/H₂O with TFA, Gemini-NX column) as aTFA salt. ES/MS m/z: 443.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.67-11.50 (m, 2H), 8.42 (d, J=1.6 Hz, 1H), 8.06 (d, J=6.1 Hz, 1H),7.99 (s, 1H), 7.65 (s, 1H), 7.47 (s, 1H), 7.47-7.43 (m, 1H), 7.43-7.38(m, 2H), 4.44-4.34 (m, 1H), 4.15 (t, J=9.1 Hz, 1H), 3.87 (t, J=7.4, 6.1Hz, 1H), 3.60 (dd, J=9.8, 5.7 Hz, 1H), 2.88-2.75 (m, 2H), 2.75-2.66 (m,1H), 2.02 (dt, J=8.9, 5.4 Hz, 1H), 1.88-1.80 (m, 1H), 1.21 (d, J=6.9 Hz,3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.29.

Example 296.5-(8-((1S,2S)-2-(3-(3-(trifluoromethyl)azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(3-(trifluoromethyl)azetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3-(trifluoromethyl)azetidine andpurified by RP-HPLC (5-90% MeCN/H₂O with TFA, Gemini-NX column) as a TFAsalt. ES/MS m/z: 497.08 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65-11.48(m, 2H), 8.38 (s, 1H), 8.05 (d, J=6.1 Hz, 1H), 7.94 (s, 1H), 7.62 (s,1H), 7.51 (s, 1H), 7.51-7.48 (m, 1H), 7.45-7.40 (m, 2H), 4.59-4.48 (m,1H), 4.40-4.33 (m, 1H), 4.29 (t, J=9.7 Hz, 1H), 4.00 (s, 1H), 3.71-3.61(m, 1H), 2.91-2.82 (m, 1H), 2.79 (dt, J=10.1, 5.1 Hz, 1H), 2.03 (dt,J=9.6, 5.3 Hz, 1H), 1.87-1.78 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−72.73 (d, J=7.2 Hz), −75.24.

Example 297.5-(8-((1S,2S)-2-(3-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3,3-difluoroazetidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 465.10 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.54 (s, 2H), 8.33 (s, 1H), 8.03 (d, J=6.3 Hz, 1H),7.86 (s, 1H), 7.57 (s, 1H), 7.55-7.51 (m, 2H), 7.47-7.39 (m, 2H),4.88-4.71 (m, 2H), 4.57-4.40 (m, 2H), 2.89 (p, J=5.3 Hz, 1H), 2.78 (dt,J=10.2, 5.1 Hz, 1H), 2.07 (dt, J=9.2, 5.0 Hz, 1H), 1.86-1.77 (m, 1H).¹⁹F NMR (376 MHz, DMSO-d6) δ −75.02, −100.16 (p, J=12.6 Hz).

Example 298.5-(8-((1S,2S)-2-(3-(3,3-dimethylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(3,3-dimethylazetidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3,3-dimethylazetidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 457.13 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.61-11.47 (m, 2H), 8.36 (d, J=1.5 Hz, 1H), 8.04 (d,J=6.1 Hz, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 7.50-7.47 (m, 1H), 7.47-7.43(m, 1H), 7.42-7.34 (m, 2H), 3.98 (s, 2H), 3.72 (s, 2H), 2.85 (ddd,J=8.9, 6.3, 4.4 Hz, 1H), 2.80-2.73 (m, 1H), 2.04 (dt, J=8.9, 5.4 Hz,1H), 1.81 (dt, J=8.8, 5.5 Hz, 1H), 1.24 (s, 6H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.12.

Example 299.5-(8-((1S,2S)-2-(4-((3R,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-((3R,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with (3R,4R)-3,4-difluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 479.09 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.54 (s, 2H), 8.32 (s, 1H), 8.02 (d, J=6.4 Hz, 1H),7.85 (s, 1H), 7.56 (s, 1H), 7.54 (d, J=8.1 Hz, 2H), 7.38-7.29 (m, 2H),5.37 (dd, J=48.7, 32.8 Hz, 2H), 4.04-3.76 (m, 4H), 2.91-2.83 (m, 1H),2.79 (t, J=10.9 Hz, 2H), 2.10 (dt, J=9.6, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.01, −188.33 (dd, J=71.3, 34.2 Hz), −190.01-−190.64 (m).

Example 300.5-(8-((1S,2S)-2-(3-((3R,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-((3R,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with (3R,4R)-3,4-difluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 479.09 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.53 (s, 2H), 8.31 (s, 1H), 8.02 (d, J=6.4 Hz, 1H),7.83 (s, 1H), 7.55 (s, 1H), 7.46-7.43 (m, 1H), 7.43-7.35 (m, 3H), 5.36(dd, J=49.1, 34.2 Hz, 2H), 4.07-3.69 (m, 4H), 2.88 (dtd, J=8.8, 6.1,5.5, 3.0 Hz, 1H), 2.78 (tt, J=9.4, 5.0 Hz, 1H), 2.07 (td, J=9.0, 4.3 Hz,1H), 1.82 (dq, J=10.7, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.89,−188.04-−188.56 (m), −190.04-−190.60 (m).

Example 301.5-(8-((1S,2S)-2-(4-((3S,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-((3S,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with (3S,4R)-3,4-difluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 479.07 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.64-11.42 (m, 2H), 8.34 (d, J=1.5 Hz, 1H), 8.03 (d,J=6.4 Hz, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 7.54-7.46 (m, 2H), 7.33 (dd,J=8.6, 2.4 Hz, 2H), 5.50-5.09 (m, 2H), 3.95-3.80 (m, 4H), 2.83 (ddq,J=22.6, 13.5, 4.6 Hz, 2H), 2.13-2.05 (m, 1H), 1.87-1.77 (m, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.08, −204.12-−204.79 (m), −206.15-−206.59 (m).

Example 302.5-(8-((1S,2S)-2-(3-((3S,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-((3S,4R)-3,4-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with (3S,4R)-3,4-difluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 479.10 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.62-11.48 (m, 2H), 8.35 (s, 1H), 8.03 (d, J=6.1 Hz,1H), 7.90 (s, 1H), 7.59 (s, 1H), 7.45-7.36 (m, 4H), 5.49-5.15 (m, 2H),3.87 (dq, J=18.2, 6.8, 5.3 Hz, 2H), 3.64 (dd, J=22.4, 14.3 Hz, 2H),2.90-2.82 (m, 1H), 2.82-2.74 (m, 1H), 2.04 (dt, J=10.3, 5.3 Hz, 1H),1.83 (dt, J=8.6, 5.4 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.10,−204.21-−204.79 (m), −205.91-−206.60 (m).

Example 303.5-(8-((1S,2S)-2-(4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with 3,3,4,4-tetrafluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 515.09 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.53 (s, 2H), 8.29 (s, 1H), 8.01 (d, J=6.2 Hz, 1H),7.80 (s, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.53 (s, 1H), 7.36 (d, J=8.1 Hz,2H), 4.36-4.14 (m, 4H), 2.88 (dt, J=9.6, 5.5 Hz, 1H), 2.79 (dt, J=9.8,5.2 Hz, 1H), 2.14 (dt, J=9.7, 5.2 Hz, 1H), 1.85-1.77 (m, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −74.89, −122.40-−123.00 (m), −123.80-−124.44 (m).

Example 304.5-(8-((1S,2S)-2-(3-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3,3,4,4-tetrafluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 515.09 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.56-11.46 (m, 2H), 8.28 (s, 1H), 8.01 (d, J=6.2 Hz,1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 7.45-7.38 (m, 3H),4.38-4.12 (m, 4H), 2.91 (dt, J=9.6, 5.5 Hz, 1H), 2.77 (dt, J=10.1, 5.3Hz, 1H), 2.11 (dt, J=9.6, 5.3 Hz, 1H), 1.85-1.78 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −74.74, −122.55-−122.89 (m), −123.85-−124.18 (m).

Example 305.5-(8-((1S,2S)-2-(4-(3,3-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3,3-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with 3,3-difluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 479.10 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.53 (s, 2H), 8.31 (d, J=1.4 Hz, 1H), 8.02 (d, J=6.4Hz, 1H), 7.82 (s, 1H), 7.53 (d, J=9.4 Hz, 2H), 7.50 (s, 1H), 7.37-7.25(m, 2H), 3.90 (t, J=13.1 Hz, 2H), 3.74-3.66 (m, 4H), 2.90-2.81 (m, 1H),2.81-2.73 (m, 1H), 2.44-2.35 (m, 2H), 2.11 (dt, J=9.4, 5.2 Hz, 1H), 1.81(dt, J=10.5, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.93,−100.62-−101.02 (m), −101.82-−102.23 (m).

Example 306.5-(8-((1S,2S)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(3,3-difluoropyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3,3-difluoropyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 479.04 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.63-11.49 (m, 2H), 8.36 (s, 1H), 8.04 (d, J=6.1 Hz,1H), 7.90 (s, 1H), 7.59 (s, 1H), 7.46-7.35 (m, 4H), 3.90 (t, J=13.1 Hz,2H), 3.76-3.64 (m, 2H), 2.91-2.82 (m, 1H), 2.78 (dt, J=10.0, 5.3 Hz,1H), 2.48-2.37 (m, 2H), 2.06 (dt, J=9.8, 5.3 Hz, 1H), 1.83 (dt, J=10.9,Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.10, −100.54-−100.75 (m),−101.78-−102.00 (m).

Example 307.5-(8-((1S,2S)-2-(4-(3,3-dimethylpyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3,3-dimethylpyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing azetidine hydrochloride with 3,3-dimethylpyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 471.15 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.53 (s, 2H), 8.31 (s, 1H), 8.02 (d, J=6.4 Hz, 1H),7.84 (s, 1H), 7.55 (s, 1H), 7.46 (dd, J=15.7, 7.9 Hz, 2H), 7.30 (d,J=8.1 Hz, 2H), 3.57-3.51 (m, 1H), 3.51-3.46 (m, 1H), 3.22 (s, 1H), 3.17(s, 1H), 2.87-2.80 (m, 1H), 2.77 (dt, J=9.9, 5.5 Hz, 1H), 2.13-2.05 (m,1H), 1.83-1.76 (m, 1H), 1.68 (t, J=7.3 Hz, 1H), 1.64 (t, J=7.3 Hz, 1H),1.10 (s, 3H), 0.97 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.97.

Example 308.5-(8-((1S,2S)-2-(3-(3,3-dimethylpyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(3,3-dimethylpyrrolidine-1-carbonyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3,3-dimethylpyrrolidinehydrochloride and purified by RP-HPLC (5-90% MeCN/H₂O with TFA,Gemini-NX column) as a TFA salt. ES/MS m/z: 471.16 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.54 (s, 2H), 8.32 (s, 1H), 8.03 (d, J=6.4 Hz, 1H),7.84 (s, 1H), 7.54 (s, 1H), 7.41-7.31 (m, 4H), 3.55 (t, J=7.3 Hz, 1H),3.48 (t, J=7.0 Hz, 1H), 3.23 (s, 1H), 3.16 (s, 1H), 2.86 (dt, J=5.8 Hz,1H), 2.77 (dt, J=9.8, 5.4 Hz, 1H), 2.07 (dt, J=11.1, 5.4 Hz, 1H),1.85-1.77 (m, 1H), 1.69 (t, J=7.2 Hz, 1H), 1.64 (t, J=7.0 Hz, 1H), 1.11(s, 3H), 0.98 (d, J=2.9 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.89.

Example 309.5-(8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(2-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 430.05 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55(d, J=7.7 Hz, 2H), 8.36 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.91 (s, 1H),7.66 (s, 1H), 7.51-7.25 (m, 4H), 3.04 (dt, J=9.6, 5.8 Hz, 1H), 2.74 (dt,J=9.9, Hz, 1H), 2.09 (dt, J=9.1, 5.4 Hz, 1H), 1.84 (dt, J=8.3, 5.3 Hz,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −56.92, −75.19.

Example 310.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrileand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 407.00 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53(s, 2H), 8.02 (d, J=6.4 Hz, 1H), 7.82 (dd, J=1.6 Hz, 1H), 7.69 (dd,J=8.1, 1.6 Hz, 1H), 7.57-7.52 (m, 2H), 7.49 (t, J=7.9 Hz, 1H), 3.11 (dt,J=9.2, 5.8 Hz, 1H), 2.86-2.77 (m, 1H), 2.23 (ddd, J=9.0, 6.1, 4.8 Hz,1H), 1.94-1.85 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.03, −118.11(dd, J=10.2, 7.7 Hz), −155.57 (d, J=7.0 Hz).

Example 311.5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrile

5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrileas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)nicotinonitrileand purified by RP-HPLC (10-60% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 372.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.67-11.48 (m, 2H), 8.87 (d, J=1.9 Hz, 1H), 8.85 (d, J=2.3 Hz, 1H),8.38 (d, J=1.5 Hz, 1H), 8.21 (t, J=2.1 Hz, 1H), 8.05 (d, J=6.1 Hz, 1H),7.93 (s, 1H), 7.67 (s, 1H), 2.98-2.90 (m, 1H), 2.90-2.83 (m, 1H), 2.19(dt, J=8.9, 5.4 Hz, 1H), 1.94 (dt, J=8.6, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.29.

Example 312.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N-methylbenzamide

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-N-methylbenzamideas a racemate was prepared in the manner described for Example 289, butreplacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 2 M methylamine in THF andpurified by RP-HPLC (5-90% MeCN/H₂O with TFA, Gemini-NX column) as a TFAsalt. ES/MS m/z: 421.04 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58-11.48(m, 2H), 8.37 (q, J=4.4 Hz, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.83-7.74 (m,2H), 7.54 (d, J=7.1 Hz, 1H), 7.47 (s, 1H), 7.34-7.30 (m, 2H), 2.88 (ddd,J=9.0, 6.5, 4.8 Hz, 1H), 2.77 (d, J=4.5 Hz, 3H), 2.76-2.71 (m, 1H), 2.13(dt, J=8.9, 5.3 Hz, 1H), 1.85-1.77 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−74.89, −155.59 (d, J=7.3 Hz).

Example 313.5-(8-((1S,2S)-2-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere prepared as a racemic mixture in the manner described for Example289, but replacing4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid with racemic4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzoicacid and azetidine hydrochloride with 3,3-difluoroazetidinehydrochloride and isolated by filtration as an HCl salt. ES/MS m/z:483.01 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 2H), 8.02 (s, 1H),7.66-7.61 (m, 2H), 7.54 (d, J=7.1 Hz, 1H), 7.48 (s, 1H), 7.38-7.32 (m,2H), 4.97-4.64 (m, 2H), 4.64-4.26 (m, 2H), 2.92-2.85 (m, 1H), 2.79-2.71(m, 1H), 2.16 (dt, J=10.6, 5.5 Hz, 1H), 1.81 (dt, J=8.7, 5.3 Hz, 1H).¹⁹F NMR (376 MHz, DMSO-d6) δ −100.10 (p, J=12.6 Hz), −155.57 (d, J=7.1Hz).

5-(8-((1S,2S)-2-(4-(3,3-difluoroazetidine-1-carbonyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas separated by SFC using 35% EtOH on a OJ-H column. Example 313 wasthe second eluting peak. ES/MS m/z: 483.02 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.60-11.49 (m, 2H), 8.03 (d, J=6.4 Hz, 1H), 7.67-7.60 (m,2H), 7.54 (d, J=7.1 Hz, 1H), 7.48 (s, 1H), 7.37-7.31 (m, 2H), 4.84-4.67(m, 2H), 4.55-4.41 (m, 2H), 2.88 (ddd, J=9.0, 6.5, 4.4 Hz, 1H),2.78-2.72 (m, 1H), 2.16 (dt, J=8.9, Hz, 1H), 1.81 (dt, J=8.8, 5.5 Hz,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.18, −100.11 (p, J=12.6 Hz),−155.56 (d, J=7.1 Hz).

Example 314. methyl(1R,5S,6r)-3-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate

To 5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(100 mg, mmol) and methyl(1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (64 mg,0.36 mmol, 1.1 equiv) in NMP (3 mL) was added DIPEA (0.13 mL, 0.71 mmol,2.2 equiv) and the mixture was heated to 130° C. After 24 h, thematerial was purified by RP-HPLC (5-60% MeCN/H₂O with TFA, Gemini-NXcolumn) to afford methyl(1R,5S,6r)-3-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylateas a TFA salt. ES/MS m/z: 369.08 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.39 (d, J=2.0 Hz, 1H), 11.35 (d, J=6.4 Hz, 1H), 8.02 (d, J=1.2 Hz,1H), 7.92 (d, J=6.2 Hz, 1H), 7.54 (d, J=1.2 Hz, 1H), 6.57 (s, 1H),4.45-4.23 (m, 2H), 3.85-3.77 (m, 2H), 3.63 (s, 3H), 2.32-2.26 (m, 2H),1.62 (t, J=3.1 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.90.

Example 315.5-(8-(2-azaspiro[4.4]nonan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-azaspiro[4.4]nonan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 314, but replacingmethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloridewith 2-azaspiro[4.4]nonane and purified by RP-HPLC (5-90% MeCN/H₂O withTFA, Gemini-NX column) as a TFA salt. ES/MS m/z: 353.10 [M+H]. ¹H NMR(400 MHz, DMSO-d6) δ 11.39 (s, 1H), 11.36 (d, J=6.2 Hz, 1H), 8.06-8.01(m, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.59 (s, 1H), 6.59 (s, 1H), 3.88-3.49(m, 4H), 1.91 (t, J=6.9 Hz, 2H), 1.73-1.64 (m, 4H), 1.64-1.51 (m, 4H).¹⁹F NMR (376 MHz, DMSO-d6) δ −75.15.

Example 316.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazineand isolated by filtration as a HCl salt. ES/MS m/z: 468.00 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.62-11.48 (m, 2H), 8.35 (s, 1H), 8.14 (s,1H), 8.04 (d, J=6.0 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.68(s, 1H), 7.59 (s, 1H), 7.39 (dd, J=8.8, 1.6 Hz, 1H), 5.44 (q, J=9.2 Hz,2H), 2.96-2.89 (m, 1H), 2.81-2.74 (m, 1H), 2.04 (dt, J=10.0, 5.3 Hz,1H), 1.85 (dt, J=8.6, 5.4 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.15(t, J=9.1 Hz).

Example 317.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazineand isolated by filtration as a HCl salt. ES/MS m/z: 486.00 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.58-11.47 (m, 2H), 8.13 (s, 1H), 8.03 (d,J=6.5 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J=7.1 Hz,1H), 7.47 (s, 1H), 7.39 (dd, J=8.7, 1.6 Hz, 1H), 5.43 (q, J=9.2 Hz, 2H),2.95 (ddd, J=9.1, 6.3, 4.4 Hz, 1H), 2.76-2.68 (m, 1H), 2.14-2.03 (m,1H), 1.81 (ddd, J=8.7, 6.3, 4.8 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−70.16 (t, J=9.2 Hz), −155.62 (d, J=7.0 Hz).

Example 318.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 468.00 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.61(dd, J=6.2, 2.0 Hz, 1H), 11.57 (d, J=2.0 Hz, 1H), 8.40 (d, J=1.5 Hz,1H), 8.16 (s, 1H), 8.06 (d, J=6.2 Hz, 1H), 7.97 (d, J=1.6 Hz, 1H), 7.74(d, J=8.1 Hz, 2H), 7.67 (s, 1H), 7.11 (dd, J=8.3, 1.3 Hz, 1H), 5.41 (q,J=9.1 Hz, 2H), 2.96 (ddd, J=9.0, 6.4, 4.3 Hz, 1H), 2.83 (dt, J=9.9, 5.4Hz, 1H), 2.08 (dt, J=8.9, 5.3 Hz, 1H), 1.94 (dt, J=8.5, 5.4 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −70.07 (t, J=9.1 Hz), −75.32.

Example 319.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazineand isolated by filtration as a HCl salt. ES/MS m/z: 486.00 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.58-11.47 (m, 2H), 8.13 (s, 1H), 8.03 (d,J=6.5 Hz, 1H), 7.74 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.54 (d, J=7.1 Hz,1H), 7.47 (s, 1H), 7.39 (dd, J=8.7, 1.6 Hz, 1H), 5.43 (q, J=9.2 Hz, 2H),2.95 (ddd, J=9.1, 6.3, 4.4 Hz, 1H), 2.76-2.68 (m, 1H), 2.14-2.03 (m,1H), 1.81 (ddd, J=8.7, 6.3, 4.8 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−70.16 (t, J=9.2 Hz), −155.62 (d, J=7.0 Hz).

Example 320.5-(8-(3,3-difluoro-5,5-dimethylpiperidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-5,5-dimethylpiperidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 314, but replacingmethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloridewith 3,3-difluoro-5,5-dimethylpiperidine heated for 48 h and purified byRP-HPLC (5-90% MeCN/H₂O with TFA, Gemini-NX column) as a TFA salt. ES/MSm/z: 377.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.40 (d, J=2.0 Hz, 1H),11.39-11.33 (m, 1H), 8.05 (d, J=1.1 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H),7.58 (d, J=1.2 Hz, 1H), 7.01 (s, 1H), 4.64 (t, J=12.4 Hz, 2H), 3.77 (s,2H), 1.98 (t, J=15.0 Hz, 2H), 1.03 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.15, −94.90 (p, J=13.7, 13.3 Hz).

Example 321.5-(8-((1S,2S)-2-(2-methylbenzo[d]thiazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-methylbenzo[d]thiazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazoleand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 417.02 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.65-11.50 (m, 2H), 8.39 (d, J=1.6 Hz, 1H), 8.06 (d, J=6.1 Hz, 1H),8.00-7.91 (m, 2H), 7.82 (d, J=1.6 Hz, 1H), 7.64 (s, 1H), 7.31 (dd,J=8.4, 1.8 Hz, 1H), 2.93 (ddd, J=9.1, 6.3, 4.4 Hz, 1H), 2.83 (ddd,J=8.7, 5.8, 4.2 Hz, 1H), 2.80 (s, 3H), 2.08 (dt, J=9.1, 5.3 Hz, 1H),1.89 (ddd, J=8.7, 6.4, 5.0 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.16.

Example 322.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 468.04 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.61(dd, J=6.2, 2.0 Hz, 1H), 11.57 (d, J=1.9 Hz, 1H), 8.63 (s, 1H), 8.41 (d,J=1.6 Hz, 1H), 8.06 (d, J=6.2 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.77 (s,1H), 7.70 (d, J=8.4 Hz, 1H), 7.67 (s, 1H), 7.27 (dd, J=8.5, 1.6 Hz, 1H),5.41 (q, J=9.2 Hz, 2H), 2.96 (ddd, J=9.1, 6.4, 4.3 Hz, 1H), 2.84-2.75(m, 1H), 2.06 (dt, J=9.0, 5.3 Hz, 1H), 1.95-1.86 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −70.70 (t, J=9.2 Hz), −75.38.

Example 323.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 486.00 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.58-11.47 (m, 2H), 8.56 (s, 1H), 8.03 (d, J=6.4 Hz, 1H), 7.74 (s, 1H),7.66 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.1 Hz, 1H), 7.48 (s, 1H), 7.26 (dd,J=8.4, 1.5 Hz, 1H), 5.39 (q, J=9.2 Hz, 2H), 3.02 (ddd, J=9.2, 6.2, 4.3Hz, 1H), 2.73 (dt, J=9.5, 5.3 Hz, 1H), 2.14 (dt, J=8.9, 5.2 Hz, 1H),1.84 (dt, J=8.5, 5.2 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.74 (t,J=9.1 Hz), −75.32, −155.55 (d, J=7.0 Hz).

Example 324.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 468.03 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.64(dd, J=6.3, 2.0 Hz, 1H), 11.59 (d, J=2.0 Hz, 1H), 8.65 (s, 1H), 8.46 (d,J=1.6 Hz, 1H), 8.08 (d, J=6.2 Hz, 1H), 8.07 (d, J=1.7 Hz, 1H), 7.76 (d,J=8.5 Hz, 1H), 7.71 (s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.35 (dd, J=8.5,1.6 Hz, 1H), 5.43 (q, J=9.2 Hz, 2H), 2.90 (ddd, J=9.1, 6.4, 4.3 Hz, 1H),2.86-2.78 (m, 1H), 2.01 (dt, J=8.9, 5.4 Hz, 1H), 1.92 (dt, J=8.5, 5.4Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.74 (t, J=9.2 Hz), −75.37.

Example 325.5-(8-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(8,8-difluoro-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 314, but replacingmethyl (1R,5S,6r)-3-azabicyclo[3.1.0]hexane-6-carboxylate hydrochloridewith 8,8-difluoro-6-azaspiro[3.4]octane and purified by filtration as aHCl salt. ES/MS m/z: 375.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.40 (s,1H), 11.37 (d, J=5.4 Hz, 1H), 8.05 (d, J=1.1 Hz, 1H), 7.92 (d, J=5.9 Hz,1H), 7.56 (d, J=1.1 Hz, 1H), 6.57 (s, 1H), 4.42-4.22 (m, 2H), 4.16-3.97(m, 2H), 2.39-2.28 (m, 2H), 2.10-2.01 (m, 2H), 2.01-1.93 (m, 1H),1.94-1.79 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −116.97.

Example 326.5-(8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-methyl-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 400.02 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53(s, 2H), 8.30 (s, 1H), 8.02 (d, J=6.3 Hz, 1H), 7.98 (s, 1H), 7.82 (s,1H), 7.68 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.03 (d, J=8.6Hz, 1H), 4.02 (s, 3H), 2.98 (dt, J=9.4, 5.7 Hz, 1H), 2.81 (dt, J=9.8,5.4 Hz, 1H), 2.17-2.08 (m, 1H), 1.96-1.87 (m, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −74.91.

Example 327.5-(8-((1S,2S)-2-(3-(trifluoromethyl)benzo[d]isoxazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-(trifluoromethyl)benzo[d]isoxazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a racemate was prepared in the manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith racemic5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-(trifluoromethyl)benzo[d]isoxazoleand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NX column) asa TFA salt. ES/MS m/z: 455.00 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53(s, 2H), 8.31 (d, J=1.4 Hz, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.98 (d, J=8.9Hz, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.78 (dd, J=9.0, 1.8 Hz, 1H), 7.57(s, 1H), 3.09 (ddd, J=9.0, 6.2, 4.6 Hz, 1H), 2.87-2.80 (m, 1H),2.18-2.10 (m, 1H), 1.93 (dt, J=8.8, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −62.09, −74.93.

Example 328.5-(2-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To2-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-(40mg, 0.09 mmol) in DMF (0.5 mL) was added TMSI (0.09 mL, 0.63 mmol).After 4 h, additional TMSI (0.05 mL, 0.35 mmol) was added. After anadditional 17 h, MeOH was added to the mixture and the solids wereisolated by filtration to afford5-(2-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a HI salt. ES/MS m/z: 397.00 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.49-11.36 (m, 2H), 8.23 (s, 1H), 7.93 (d, J=6.1 Hz, 1H), 6.67 (s, 1H),4.54-4.18 (m, 2H), 3.99-3.66 (m, 2H), 1.20 (s, 6H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −115.35 (t, J=12.8 Hz).

Example 329.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a solution of Example 607 (115.6 mg, 0.02 mmol) in DMF (0.7 mL) wasadded SelectFluor (11 mg, 0.03 mmol) and stirred for 16 h. Directpurification of the reaction mixture was accomplished by reverse phaseHPLC (5-90% MeCN/H₂O with 0.1% TFA) affording5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 554.00 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.42 (m,2H), 8.04 (d, J=6.4 Hz, 1H), 7.94 (s, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.56(d, J=7.1 Hz, 1H), 7.52 (s, 1H), 7.37 (dd, J=8.6, 1.1 Hz, 1H), 5.62 (q,J=9.2, 8.8 Hz, 2H), 3.16-3.06 (m, 1H), 2.88-2.76 (m, 1H), 2.26-2.17 (m,1H), 1.97-1.82 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −60.43, −70.03 (t,J=9.0 Hz), −155.55 (d, J=7.0 Hz).

Examples 330 and 331.(S)-5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

A solution of8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(100 mg, 0.19 mmol) in 1:1 1N HCl:MeOH (2 mL) was heated to 80° C. After3 hours, the reaction solvent was evaporated and the residue waspurified with Prep HPLC, affording5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 496.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.49-11.28 (m,2H), 8.53 (d, J=5.3 Hz, 1H), 8.09 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz,1H), 7.59 (d, J=1.1 Hz, 1H), 7.49 (dd, J=5.4, 1.4 Hz, 1H), 7.43 (s, 1H),6.65 (s, 1H), 6.01 (dd, J=8.9, 5.2 Hz, 1H), 4.82-4.36 (m, 4H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −64.03, −75.18, −108.34, −119.74 (d, J=236.7 Hz).

5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas purified with chiral SFC column to afford two single enantiomers(S)-5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.

Example 330:(S)-5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 496.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.49-11.28 (m,2H), 8.53 (d, J=5.3 Hz, 1H), 8.09 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz,1H), 7.59 (d, J=1.1 Hz, 1H), 7.49 (dd, J=5.4, 1.4 Hz, 1H), 7.43 (s, 1H),6.65 (s, 1H), 6.01 (dd, J=8.9, 5.2 Hz, 1H), 4.82-4.36 (m, 4H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −64.03, −75.18, −108.34, −119.74 (d, J=236.7 Hz).And

Example 331:(R)-5-(8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 496.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.49-11.28 (m,2H), 8.53 (d, J=5.3 Hz, 1H), 8.09 (d, J=1.1 Hz, 1H), 7.95 (d, J=6.1 Hz,1H), 7.59 (d, J=1.1 Hz, 1H), 7.49 (dd, J=5.4, 1.4 Hz, 1H), 7.43 (s, 1H),6.65 (s, 1H), 6.01 (dd, J=8.9, 5.2 Hz, 1H), 4.82-4.36 (m, 4H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −64.03, −75.18, −108.34, −119.74 (d, J=236.7 Hz).

Examples 332 and 333.(R)-5-(8-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(S)-5-(8-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas purified with chiral SFC column to afford two single enantiomer(R)-5-(8-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneES/MS m/z: 494.20 [M+H]. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.18 (s,2H), 8.11 (d, J=3.0 Hz, 1H), 8.04 (d, J=6.4 Hz, 1H), 7.97 (d, J=1.6 Hz,1H), 7.70 (d, J=1.6 Hz, 1H), 7.62 (dd, J=9.0, 3.0 Hz, 1H), 7.01 (s, 1H),6.98-6.47 (m, 2H), 5.88 (dq, J=8.3, 4.3 Hz, 1H), 4.59-4.32 (m, 3H). ¹⁹FNMR (377 MHz, Acetonitrile-d3) δ −77.24, −83.60 (d, J=73.9 Hz),−108.66-−110.24 (m), —121.52-−122.84 (m). and(S)-5-(8-(4-((5-(difluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 494.20 [M+H]. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.18 (s,2H), 8.11 (d, J=3.0 Hz, 1H), 8.04 (d, J=6.4 Hz, 1H), 7.97 (d, J=1.6 Hz,1H), 7.70 (d, J=1.6 Hz, 1H), 7.62 (dd, J=9.0, 3.0 Hz, 1H), 7.01 (s, 1H),6.98-6.47 (m, 2H), 5.88 (dq, J=8.3, 4.3 Hz, 1H), 4.59-4.32 (m, 3H). ¹⁹FNMR (377 MHz, Acetonitrile-d3) δ −77.24, −83.60 (d, J=73.9 Hz),−108.66-−110.24 (m), −121.52-−122.84 (m).

Examples 334 and 335.(R)-5-(8-(3,3-difluoro-4-((5-(trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-((5-(trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl-pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Examples 330 and 331 replacingIntermediate 514 with Intermediate 516 and purified by RP-HPLC as a TFAsalt.

5-(8-(3,3-difluoro-4-((5-(trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas separated with chiral SFC column to afford two single enantiomers(S)-5-(8-(4-((5-(1,1-difluoroethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-((5-trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.

Example 334:(R)-5-(8-(4-((5-(1,1-trifluoromethoxy)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneES/MS m/z: 512.20 [M+H]. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.16 (s,2H), 8.24 (d, J=2.9 Hz, 1H), 8.03 (d, J=6.4 Hz, 1H), 7.95 (d, J=1.5 Hz,1H), 7.77-7.70 (m, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.08-6.87 (m, 2H), (tt,J=8.6, 3.9 Hz, 1H), 4.61-4.34 (m, 3H), 4.21 (d, J=12.4 Hz, 1H). ¹⁹F NMR(376 MHz, Acetonitrile-d3) δ −60.13, −77.24 (d, J=1.5 Hz),−106.81-−111.83 (m), −122.07 (d, J=240.9 Hz).

Example 335:(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneES/MS m/z: 512.20 [M+H]. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.16 (s,2H), 8.24 (d, J=2.9 Hz, 1H), 8.03 (d, J=6.4 Hz, 1H), 7.95 (d, J=1.5 Hz,1H), 7.77-7.70 (m, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.08-6.87 (m, 2H), (tt,J=8.6, 3.9 Hz, 1H), 4.61-4.34 (m, 3H), 4.21 (d, J=12.4 Hz, 1H). ¹⁹F NMR(376 MHz, Acetonitrile-d3) δ −60.13, −77.24 (d, J=1.5 Hz),−106.81-−111.83 (m), −122.07 (d, J=240.9 Hz).

Examples 336 and 337.(R)-5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(S)-5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as in the manner described for Examples 330 and 331replacing Intermediate 514 with Intermediate 517 and purified by RP-HPLCas a TFA salt.

5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas purified with chiral SFC column to afford two single enantiomers(S)-5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.

Example 336:(R)-5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneES/MS m/z: 562.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.17 (s, 2H),8.23 (d, J=2.9 Hz, 1H), 8.06 (d, J=6.4 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H),7.74 (dd, J=10.3, 2.3 Hz, 2H), 7.13-6.81 (m, 2H), 5.91 (h, J=4.3 Hz,1H), 4.54-4.34 (m, 3H), 4.20 (dt, J=12.3, 2.6 Hz, 1H). ¹⁹F NMR (376 MHz,Acetonitrile-d3) δ −77.25, −87.18, −89.01, −108.05-−111.75 (m),−120.35-−123.36 (m). Example 337:(S)-5-(8-(3,3-difluoro-4-((5-(perfluoroethoxy)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneES/MS m/z: 562.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.17 (s, 2H),8.23 (d, J=2.9 Hz, 1H), 8.06 (d, J=6.4 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H),7.74 (dd, J=10.3, 2.3 Hz, 2H), 7.13-6.81 (m, 2H), 5.91 (h, J=4.3 Hz,1H), 4.54-4.34 (m, 3H), 4.20 (dt, J=12.3, 2.6 Hz, 1H). ¹⁹F NMR (376 MHz,Acetonitrile-d3) δ −77.25, −87.18, −89.01, −108.05-−111.75 (m),−120.35-−123.36 (m).

Examples 338 and 339.(R)-6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrileand(S)-6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrile

6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrilewas prepared in the manner described for Examples 330 and 331 replacingIntermediate 514 with Intermediate 518 and purified by RP-HPLC as a TFAsalt.

6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrilewas purified with chiral SFC column to afford two single enantiomers(S)-6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrileand(R)-6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrile.

Example 338:(R)-6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrile.ES/MS m/z: 453.20. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.30 (d, J=12.5Hz, 2H), 8.61 (d, J=2.3 Hz, 1H), 8.15-8.02 (m, 2H), 8.02 (d, J=1.8 Hz,1H), 7.79 (d, J=1.8 Hz, 1H), 7.17 (s, 1H), 7.04 (d, J=8.7 Hz, 1H), 6.00(ddt, J=8.3, 4.9, 3.1 Hz, 1H), 4.46 (td, J=18.2, 10.3 Hz, 3H), 4.19 (dt,J=12.1, 2.7 Hz, 1H). ¹⁹F NMR (377 MHz, Acetonitrile-d3) δ −77.23,−109.58 (d, J=241.9 Hz), −121.92 (d, J=241.8 Hz).

(S)-6-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)nicotinonitrile.ES/MS m/z: 453.20. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.30 (d, J=12.5Hz, 2H), 8.61 (d, J=2.3 Hz, 1H), 8.15-8.02 (m, 2H), 8.02 (d, J=1.8 Hz,1H), 7.79 (d, J=1.8 Hz, 1H), 7.17 (s, 1H), 7.04 (d, J=8.7 Hz, 1H), 6.00(ddt, J=8.3, 4.9, 3.1 Hz, 1H), 4.46 (td, J=18.2, 10.3 Hz, 3H), 4.19 (dt,J=12.1, 2.7 Hz, 1H). ¹⁹F NMR (377 MHz, Acetonitrile-d3) δ −77.23,−109.58 (d, J=241.9 Hz), −121.92 (d, J=241.8 Hz).

Example 340.5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 330, but replacing8-(3,3-difluoro-4-((4-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrazin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand purified by RP-HPLC as a TFA salt. ES/MS m/z: 497.10. ¹H NMR (400MHz, Acetonitrile-d3) δ 9.22 (s, 2H), 8.65 (s, 1H), 8.45 (d, J=1.3 Hz,1H), 8.07 (d, J=6.4 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.75 (d, J=1.6 Hz,1H), 7.10 (s, 1H), 6.04-5.84 (m, 1H), 4.61-4.37 (m, 3H), 4.26 (dt,J=12.5, 2.7 Hz, 1H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −68.01,−77.26, −106.97-−111.19 (m), −118.61-−123.19 (m).

Example 341.(S)-5-(8-(4-((4-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(4-((4-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionein the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(S)-8-(4-((4-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand purified by RP-HPLC as a TFA salt. ES/MS m/z: 478.20. ¹H NMR (400MHz, Acetonitrile-d3) δ 9.09 (d, J=14.7 Hz, 2H), 8.36 (d, J=5.3 Hz, 1H),8.00 (d, J=6.4 Hz, 1H), 7.92 (d, J=1.4 Hz, 1H), 7.62 (d, J=1.4 Hz, 1H),7.23 (d, J=5.3 Hz, 1H), 7.05 (s, 1H), 6.99-6.51 (m, 2H), 5.95 (d, J=4.6Hz, 1H), 4.49 (td, J=20.8, 8.3 Hz, 3H), 4.23 (d, J=12.4 Hz, 1H). ¹⁹F NMR(376 MHz, Acetonitrile-d3) δ −77.27, −108.96-−109.60 (m), −117.17 (d,J=55.4 Hz), −121.70-−122.36 (m).

Example 342.2-[(3S)-1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]oxypyridine-4-carbonitrile

2-[(3S)-1-[6-(2,4-dioxo-1H-pyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-yl]oxypyridine-4-carbonitrilein the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(S)-2-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)isonicotinonitrileand purified by RP-HPLC as a TFA salt. ES/MS m/z: 453.10. ¹H NMR (400MHz, Acetonitrile-d3) δ 9.12 (d, J=15.2 Hz, 2H), 8.41 (dd, J=5.2, 0.8Hz, 1H), 8.03-7.93 (m, 1H), 7.89 (d, J=1.2 Hz, 1H), 7.57 (d, J=1.2 Hz,1H), 7.36 (dd, J=5.2, 1.3 Hz, 1H), 7.25 (d, J=1.1 Hz, 1H), 6.76 (s, 1H),5.92 (d, J=4.3 Hz, 1H), 4.67-4.33 (m, 3H), 4.26 (d, J=12.8 Hz, 1H). ¹⁹FNMR (376 MHz, Acetonitrile-d3) δ −77.18, −109.11 (d, J=246.1 Hz),−120.61-−123.05 (m).

Example 343.5-[8-[7-(difluoromethoxy)-5-azaspiro[2.4]heptan-5-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-(8-(7-(difluoromethoxy)-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 342, but replacing6-azabicyclo[3.2.0]heptane with7-(difluoromethoxy)-5-azaspiro[2.4]heptane and purified by RP-HPLC as aTFA salt. ES/MS m/z: 391.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.11(s, 2H), 7.99 (d, J=6.2 Hz, 1H), 7.88 (d, J=1.3 Hz, 1H), 7.59 (d, J=1.3Hz, 1H), 6.76 (s, 1H), 6.48 (t, J=75.5 Hz, 1H), 4.44 (s, 1H), 4.36 (d,J=4.0 Hz, 1H), 4.27 (d, J=12.1 Hz, 1H), 4.11 (d, J=10.7 Hz, 1H), 3.64(m, 1H), 1.11-0.83 (m, 3H), 0.79 (dt, J=10.0, 5.0 Hz, 1H). ¹⁹F NMR (376MHz, Acetonitrile-d3) δ −77.04, −80.78-−82.87 (m).

Example 344.5-[8-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-(8-(7-hydroxy-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-5-azaspiro[2.4]heptan-7-ol.ES/MS m/z: 341.20. ¹H NMR (400 MHz, DMSO-d6) δ 11.37 (dd, J=10.7, 4.1Hz, 2H), 8.04 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.3Hz, 1H), 6.57 (s, 1H), 3.79 (d, J=6.5 Hz, 1H), 2.58-2.51 (m, 4H), 0.89(dt, J=11.1, 5.0 Hz, 1H), 0.66 (dt, J=16.5, 5.5 Hz, 3H).

Example 345.5-[8-[7-[[5-(trifluoromethyl)-2-pyridyl]oxy]-5-azaspiro[2.4]heptan-5-yl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-(8-(7-((5-(trifluoromethyl)pyrazin-2-yl)oxy)-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionein the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(7-((5-(trifluoromethyl)pyridin-2-yl)oxy)-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]and purified by RP-HPLC as a TFA salt. ES/MS m/z: 486.20. ¹H NMR (400MHz, Acetonitrile-d3) δ 9.20 (d, J=33.4 Hz, 2H), 8.51 (d, J=2.4 Hz, 1H),8.05-7.98 (m, 1H), 7.96 (dd, J=8.8, 2.6 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H),7.66 (d, J=1.4 Hz, 1H), 7.03-6.84 (m, 2H), 4.79 (d, J=12.8 Hz, 1H), 4.21(d, J=10.9 Hz, 1H), 4.17-4.01 (m, 2H), 3.34 (q, J=7.8 Hz, 1H), 2.80-2.62(m, 1H), 2.41 (q, J=10.8 Hz, 1H), 2.35-2.19 (m, 1H), 1.68 (dq, J=11.9,8.8 Hz, 1H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −62.59, −77.09.

Example 346.5-(8-(3,3-difluoro-4-phenylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-phenylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3,3-difluoro-4-phenylpyrrolidinereplacing 3,3,4,4-tetrafluoropyrrolidine and purified by RP-HPLC. ES/MSm/z: 411.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.51-11.28 (m, 2H), 8.09(d, J=1.2 Hz, 1H), 7.96 (d, J=6.1 Hz, 1H), 7.59 (d, J=1.2 Hz, 1H),7.47-7.22 (m, 6H), 6.68 (s, 1H), 4.52 (d, J=30.3 Hz, 2H), 4.18 (s, 2H).¹⁹F NMR (377 MHz, DMSO-d6) δ −75.10, −108.01.

Example 347.(R)-5-(8-(3-(difluoromethoxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3-(difluoromethoxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(R)-8-(3-(difluoromethoxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazineand purified by RP-HPLC. ES/MS m/z: 365.20. ¹H NMR (400 MHz, DMSO-d6) δ11.50-11.10 (m, 2H), 8.06 (d, J=1.3 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H),7.59 (d, J=1.3 Hz, 1H), 7.05-6.50 (m, 2H), 5.16-4.90 (m, 1H), 2.26(dddd, J=19.5, 10.7, 8.0, 4.0 Hz, 2H). ¹⁹F NMR (377 MHz, DMSO-d6) δ−75.33, −81.14 (d, J=75.5 Hz).

Example 348.(S)-5-(8-(3-(difluoromethoxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(3-(difluoromethoxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(S)-8-(3-(difluoromethoxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 365.20. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.16 (s, 2H),8.03 (d, J=6.3 Hz, 1H), 7.93 (d, J=1.6 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H),6.94 (s, 1H), 6.50 (t, J=75.3 Hz, 1H), 5.02 (p, J=3.7 Hz, 1H), 4.12 (d,J=4.8 Hz, 2H), 3.90 (q, J=9.5, 9.0 Hz, 2H), 2.32 (tt, J=6.1, 3.7 Hz,2H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −77.12, −83.13 (dd, J=75.2,5.4 Hz).

Example 349.5-(8-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7-methoxy-5-azaspiro[2.4]heptan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 7-methoxy-5-azaspiro[2.4]heptane. ES/MSm/z: 355.20. ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (dd, J=10.5, 4.1 Hz, 2H),8.05 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.59 (s, 1H), 6.57 (s,1H), 3.52 (d, J=3.7 Hz, 1H), 3.29 (s, 3H), 2.70 (s, 1H), 2.18 (t, J=8.1Hz, 1H), 2.02-1.81 (m, 1H), 1.04-0.93 (m, 1H), 0.84 (dt, J=9.3, 5.4 Hz,1H), 0.74-0.54 (m, 2H).

Example 350.5-(7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 361.14. ¹H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.74 (s,1H), 8.56 (d, J=6.0 Hz, 1H), 8.18 (d, J=2.2 Hz, 1H), 6.88 (s, 1H), 6.56(d, J=2.2 Hz, 1H), 4.76 (s, 2H), 1.25-0.88 (m, 4H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −107.89.

Example 351.5-(3-fluoro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 389.00. ¹H NMR (400 MHz, DMSO-d6) δ 11.56-11.23 (m, 2H), 7.99(d, J=6.1 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 6.70 (s, 1H), 4.65 (t, J=12.4Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.91, −122.77, −122.72-−122.93(m), −155.26 (d, J=7.6 Hz).

Example 352.5-(8-((1R,5S,6r)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1R,5S,6r)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with(1R,5S,6r)-6-(trifluoromethyl)-3-azabicyclo[3.1.0]hexane. ES/MS m/z:379.10. ¹H NMR (400 MHz, DMSO-d6) δ 11.56-11.20 (m, 2H), 8.03 (d, J=1.2Hz, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.55 (d, J=1.1 Hz, 1H), 6.60 (s, 1H),4.39 (s, 1H), 3.76 (d, J=11.3 Hz, 3H), 2.26 (d, J=3.2 Hz, 2H), 1.89 (tt,J=7.4, 3.6 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −63.87 (d, J=7.5 Hz),−75.07.

Example 353.5-(8-(3,3-bis(trifluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-bis(trifluoromethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith 38-[3,3-bis(trifluoromethyl)pyrrolidin-1-yl]-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 435.10. ¹H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 8.09(d, J=1.5 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.04 (s, 1H), 4.53 (s, 2H),4.09 (t, J=7.3 Hz, 2H), 2.72 (t, J=7.3 Hz, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −73.55, −78.07.

Example 354.3-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.0]hexane-1-carbonitrile

3-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.0]hexane-1-carbonitrilewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with3-azabicyclo[3.1.0]hexane-1-carbonitrile. ES/MS m/z: 336.10. ¹H NMR (400MHz, DMSO-d6) δ 11.39 (d, J=18.6 Hz, 2H), 8.04 (d, J=1.2 Hz, 1H), 7.92(d, J=6.1 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 6.61 (s, 1H), 3.89 (d, J=10.7Hz, 1H), 3.82-3.73 (m, 1H), 2.60 (dt, J=9.0, 5.0 Hz, 1H), 1.58 (dd,J=8.6, 5.4 Hz, 1H), 1.12 (t, J=5.5 Hz, 1H).

Example 355.5-(8-(1-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(1-fluoro-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 1-fluoro-3-azabicyclo[3.1.0]hexane.ES/MS m/z: 329.10. ¹H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 2H), 8.11 (d,J=1.3 Hz, 1H), 7.95 (d, J=6.4 Hz, 1H), 7.65 (d, J=1.3 Hz, 1H), 6.68 (s,1H), 4.11 (t, J=10.6 Hz, 2H), 3.92 (s, 2H), 2.37-2.19 (m, 1H), 1.63(dddd, J=16.5, 11.6, 8.1, 4.4 Hz, 1H), 1.02-0.72 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −199.67.

Example 356.5-(7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 372.10. ¹H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 11.55 (s,1H), 8.48 (d, J=7.6 Hz, 2H), 7.51 (s, 1H), 4.73 (ddd, J=14.9, 10.2, 3.8Hz, 5H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −122.69-−122.82 (m).

Example 357.5-(7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine.ES/MS m/z: 362.10. ¹H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 11.50 (s,1H), 8.48 (s, 1H), 8.39 (s, 1H), 7.42 (s, 1H), 4.66 (t, J=12.3 Hz, 2H),4.10 (s, 2H), 1.06 (dd, J=4.8, 3.1 Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−107.51 (t, J=12.5 Hz).

Example 358.5-(7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-(3,3,4,4-tetrafluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(2,4-dimethoxypyrimidin-5-yl)-7-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidineES/MS m/z: 371.10. ¹H NMR (400 MHz, DMSO-d6) δ 11.60 (d, J=6.3 Hz, 1H),11.50 (d, J=2.0 Hz, 1H), 8.37 (d, J=6.4 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H),7.22 (s, 1H), 6.49 (d, J=2.3 Hz, 1H), 4.70 (td, J=11.3, 10.8, 5.3 Hz,4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.06, −122.08 (td, J=13.8, 12.6, 5.2Hz).

Example 359.5-(8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 430.10 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.27 (d, J=1.6 Hz, 1H), 8.24 (s, 1H), 7.91 (s, 1H), 7.82(s, 1H), 7.44-7.33 (m, 2H), 7.29-7.20 (m, 2H), 2.88-2.71 (m, 2H),2.03-1.81 (m, 2H). 19F NMR (376 MHz, Methanol-d4) δ −60.15, −77.61.

Example 360.5-(8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 426.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.54 (s, 2H), 8.32 (d, J=1.3 Hz, 1H), 8.03 (d, J=6.4 Hz,1H), 7.85 (s, 1H), 7.55 (s, 1H), 7.41-7.28 (m, 2H), 7.15 (dd, J=8.4, 1.8Hz, 1H), 2.93-2.82 (m, 1H), 2.72 (ddd, J=9.0, 5.9, 4.3 Hz, 1H), 2.09(dt, J=8.0, 5.2 Hz, 1H), 1.79 (dt, J=8.9, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −49.75 (d, J=2.3 Hz), −74.85.

Example 361.5-(8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 482.20 [M+H]. ¹H NMR (400 MHz,Acetonitrile-d3) δ 9.45 (s, 1H), 9.36 (s, 1H), 8.24-8.13 (m, 3H), 8.09(t, J=2.6 Hz, 1H), 7.97 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.53(s, 1H), 7.00 (dd, J=8.8, 1.4 Hz, 1H), 4.70 (td, J=7.0, 1.8 Hz, 2H),2.98 (qt, J=10.9, 6.9 Hz, 2H), 2.81 (q, J=4.6 Hz, 1H), 2.70 (ddd,J=11.0, 6.5, 4.3 Hz, 1H), 2.54 (s, OH), 2.06-1.98 (m, 1H), 1.90 (dq,J=9.5, 6.6, 5.7 Hz, 1H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −66.76 (t,J=10.9 Hz), −77.25 (d, J=6.6 Hz).

Example 362.6-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile

6-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrilewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-carbonitrile.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 493.20 [M+H]. ¹H NMR (400 MHz,Acetonitrile-d3) δ 9.40 (s, 1H), 9.25 (s, 1H), 8.09 (s, 2H), 7.84 (d,J=9.4 Hz, 2H), 7.73 (d, J=13.1 Hz, 2H), 7.40 (d, J=8.5 Hz, 1H), 5.29 (d,J=9.3 Hz, 2H), 3.13 (dd, J=7.3, 4.7 Hz, 4H). ¹⁹F NMR (376 MHz,Acetonitrile-d3) δ −71.88 (t, J=8.7 Hz), −76.87.

Example 363.5-(8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 445.20 [M+H]. ¹H NMR (400 MHz,Acetonitrile-d3) δ 9.54 (s, 1H), 9.34 (s, 1H), 8.34 (d, J=2.9 Hz, 1H),8.23-8.11 (m, 2H), 8.06 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.65-7.44 (m,2H), 4.66 (q, J=8.4 Hz, 2H), 3.20 (dt, J=9.3, 5.2 Hz, 1H), 2.82 (ddd,J=9.1, 6.2, 4.4 Hz, 1H), 2.02 (ddd, J=8.9, 6.3, 5.2 Hz, 1H), 1.92-1.87(m, 1H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −75.34 (t, J=8.4 Hz),−77.10.

Example 364.5-(8-((1S,2S)-2-(5-(trifluoromethyl)thiazol-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(trifluoromethyl)thiazol-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(trifluoromethyl)thiazole.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 421.10 [M+H]. ¹H NMR (400 MHz,Acetonitrile-d3) δ 9.44 (s, 1H), 9.33 (s, 1H), 8.19 (d, J=2.0 Hz, 1H),8.15 (d, J=6.4 Hz, 1H), 8.12 (q, J=1.3 Hz, 1H), 8.03 (s, 1H), 7.97 (d,J=2.0 Hz, 1H), 2.31-1.99 (m, 4H). ¹⁹F NMR (377 MHz, Acetonitrile-d3) δ−55.58, −77.15.

Example 365.5-(8-((1S,2S)-2-(2-(trifluoromethyl)thiazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-(trifluoromethyl)thiazol-5-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)thiazole.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 421.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.55 (d, J=3.8 Hz, 2H), 8.34 (d, J=1.4 Hz, 1H), 8.08 (t,J=1.0 Hz, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.86 (s, 1H), 7.63 (s, 1H), 3.31(dt, J=9.8, 5.4 Hz, 1H), 2.88 (ddd, J=9.0, 6.1, 4.4 Hz, 1H), 2.29 (dt,J=8.8, 5.4 Hz, 1H), 1.88 (dt, J=9.0, 5.4 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −60.32, −75.15.

Example 366.5-(8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 404.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.53 (s, 2H), 8.44 (s, 1H), 8.32 (d, J=1.4 Hz, 1H),8.09-7.90 (m, 2H), 7.84 (s, 1H), 7.55 (s, 1H), 2.77 (dq, J=12.3, 5.9 Hz,1H), 2.71-2.59 (m, 1H), 2.11-1.91 (m, 1H), 1.79-1.59 (m, 1H). ¹⁹F NMR(377 MHz, DMSO-d6) δ −59.68, −75.03.

Example 367.5-(8-((1S,2S)-2-(4-(trifluoromethyl)thiazol-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(trifluoromethyl)thiazol-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(trifluoromethyl)thiazole.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 421.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.55 (s, 2H), 8.34 (dd, J=5.4, 1.2 Hz, 2H), 8.02 (d, J=6.4Hz, 1H), 7.85 (s, 1H), 7.63 (s, 1H), 3.51 (ddd, J=8.8, 5.9, 4.3 Hz, 1H),3.06 (ddd, J=9.1, 6.3, 4.3 Hz, 1H), 2.27-2.16 (m, 1H), 2.06-1.83 (m,1H). ¹⁹F NMR (377 MHz, DMSO-d6) δ −62.89, −75.11.

Example 368.5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 386.10 [M+H]. ¹H NMR (400 MHz,Acetonitrile-d3) δ 9.53 (s, 1H), 9.38 (s, 1H), 8.20 (d, J=2.1 Hz, 1H),8.16 (d, J=6.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 7.97 (d, J=5.6 Hz, 2H),7.70 (s, 1H), 7.33 (t, J=60.0 Hz, 1H), 2.84 (dt, J=8.6, 5.1 Hz, 1H),2.51 (ddd, J=9.2, 6.5, 4.4 Hz, 1H), 1.86-1.64 (m, 2H). ¹⁹F NMR (377 MHz,Acetonitrile-d3) δ −77.11, −95.58, −95.74.

Example 369.5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-3-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 386.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.53 (s, 2H), 8.31 (s, 1H), 8.16 (d, J=2.6 Hz, 1H),7.95-7.57 (m, 2H), 7.54 (s, 1H), 6.50 (d, J=2.7 Hz, 1H), 2.92 (dt,J=9.1, 5.8 Hz, 1H), 2.88-2.76 (m, 1H), 2.02 (dt, J=9.5, 4.9 Hz, 1H),1.81-1.66 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.93, −94.15 (d, J=2.7Hz), −94.31.

Example 370.5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 404.10 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.53 (d, J=4.6 Hz, 2H), 8.19 (s, 1H), 8.02 (d, J=6.4 Hz,1H), 7.93-7.58 (m, 2H), 7.55 (d, J=7.1 Hz, 1H), 7.46 (s, 1H), 2.77 (ddd,J=9.0, 6.2, 4.4 Hz, 1H), 2.62 (ddd, J=8.8, 5.7, 4.3 Hz, 1H), 2.05-1.95(m, 1H), 1.65 (ddd, J=8.7, 6.3, 4.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6)δ −75.20, −93.98, −94.14, −155.65 (d, J=7.3 Hz).

Example 371.5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared by chiral separation of8-((1S,2S)-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(racemic mixture) with SFC column (peak 1). ES/MS m/z: 404.10 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.53 (d, J=4.6 Hz, 2H), 8.19 (s, 1H), 8.02 (d,J=6.4 Hz, 1H), 7.93-7.58 (m, 2H), 7.55 (d, J=7.1 Hz, 1H), 7.46 (s, 1H),2.77 (ddd, J=9.0, 6.2, 4.4 Hz, 1H), 2.62 (ddd, J=8.8, 5.7, 4.3 Hz, 1H),2.05-1.95 (m, 1H), 1.65 (ddd, J=8.7, 6.3, 4.5 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.20, −93.98, −94.14, −155.65 (d, J=7.3 Hz).

Example 372.5-(8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 431.10. ¹H NMR (400 MHz, DMSO-d6) δ11.85-11.68 (m, 1H), 11.63 (d, J=1.9 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H),8.55 (d, J=1.8 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J=6.2 Hz, 1H), 7.89-7.79(m, 2H), 7.63 (d, J=8.6 Hz, 1H), 3.16-2.96 (m, 2H), 2.05-1.84 (m, 2H).¹⁹F NMR (376 MHz, DMSO-d6) δ −57.85.

Example 373.5-(8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared by chiral separation of racemic mixture of5-(8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneby SFC column (peak 1). ES/MS m/z: 431.10. ¹H NMR (400 MHz, DMSO-d6) δ11.85-11.68 (m, 1H), 11.63 (d, J=1.9 Hz, 1H), 8.63 (d, J=2.8 Hz, 1H),8.55 (d, J=1.8 Hz, 1H), 8.18 (s, 1H), 8.11 (d, J=6.2 Hz, 1H), 7.89-7.79(m, 2H), 7.63 (d, J=8.6 Hz, 1H), 3.16-2.96 (m, 2H), 2.05-1.84 (m, 2H).¹⁹F NMR (376 MHz, DMSO-d6) δ −57.85.

Example 374.5-(3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 449.10. ¹H NMR (400 MHz, DMSO-d6) δ11.57-11.51 (m, 2H), 8.60 (d, J=2.7 Hz, 1H), 8.03 (d, J=6.4 Hz, 1H),7.86-7.78 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.58-7.48 (m, 2H), 3.12 (ddd,J=8.7, 5.8, 4.2 Hz, 1H), 2.96 (ddd, J=9.0, 6.1, 4.1 Hz, 1H), 2.18-2.06(m, 1H), 1.87 (ddd, J=9.4, 5.8, 4.0 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6)δ −57.86, −75.39, −155.54 (d, J=7.0 Hz).

Example 375.5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrile

5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrilewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)picolinonitrile.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 390.10. ¹H NMR (400 MHz, DMSO-d6) δ11.56 (d, J=9.5 Hz, 2H), 8.74 (s, 1H), 8.01 (dd, J=16.7, 7.1 Hz, 2H),7.92 (dd, J=8.1, 2.1 Hz, 1H), 7.60-7.53 (m, 2H), 3.04 (q, J=6.5, 6.0 Hz,1H), 2.87 (dt, J=9.9, 5.4 Hz, 1H), 2.29 (dt, J=10.2, 5.6 Hz, 1H), 1.92(dt, J=10.4, 5.7 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.43, −155.57(d, J=7.0 Hz).

Example 376.5-(8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(6-(trifluoromethoxy)pyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 431.10. ¹H NMR (400 MHz, DMSO-d6) δ11.55 (d, J=4.7 Hz, 2H), 8.44-8.26 (m, 2H), 8.03 (d, J=6.3 Hz, 1H),7.95-7.77 (m, 2H), 7.60 (s, 1H), 7.28 (d, J=8.5 Hz, 1H), 3.00-2.88 (m,1H), 2.80 (dt, J=8.9, 5.6 Hz, 1H), 2.15 (dt, J=8.9, 5.4 Hz, 1H), 1.85(dt, J=8.7, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −55.65, −75.08.

Example 377.5-(8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 416.10. ¹H NMR (400 MHz, DMSO-d6) δ11.56 (d, J=3.9 Hz, 2H), 9.20 (d, J=1.0 Hz, 2H), 8.36 (d, J=1.4 Hz, 1H),8.04 (d, J=6.4 Hz, 1H), 7.88 (s, 1H), 7.67 (s, 1H), 3.34-3.01 (m, 2H),2.30-2.15 (m, 1H), 2.01 (ddd, J=9.4, 5.7, 4.1 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −61.20, −75.17.

Example 378.5-(3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-(trifluoromethyl)pyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 434.10. ¹H NMR (400 MHz, DMSO-d6) δ11.54 (s, 2H), 9.18 (s, 2H), 8.03 (s, 1H), 7.56 (t, J=3.5 Hz, 2H), 3.26(ddd, J=9.1, 5.6, 4.1 Hz, 1H), 3.16-3.00 (m, 1H), 2.29 (ddd, J=8.7, 6.1,4.0 Hz, 1H), 2.11-1.88 (m, 1H). ¹⁹F NMR (377 MHz, DMSO-d6) δ −61.23,−73.95, −155.48 (d, J=7.3 Hz).

Example 379.5-(8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-(difluoromethyl)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished via RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 397.20. ¹H NMR (400 MHz, DMSO-d6) δ11.57 (d, J=5.9 Hz, 2H), 8.73 (d, J=2.0 Hz, 1H), 8.37 (s, 1H), 8.05 (d,J=6.1 Hz, 1H), 8.00-7.82 (m, 2H), 7.72-7.52 (m, 2H), 7.14 (t, J=55.4 Hz,1H), 3.16-2.93 (m, 2H), 2.15-2.01 (m, 1H), 2.00-1.86 (m, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.24 (d, J=2.2 Hz), −110.86, −111.01.

Example 380.5-(8-((1S,2S)-2-(5-bromopyrimidin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1. (2,4-dimethoxypyrimidin-5-yl)boronic acid (1.38 g, 7.53 mmol),ethyl(1S,2S)-2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)cyclopropanecarboxylate(2 g, 7.53 mmol), ferrous; cyclopenta-2,4-dien-1-yl(diphenyl)phosphane;dichloromethane; dichloropalladium (615 mg, 0.75 mmol), cesium carbonate(4.9 g, 15.1 mmol) were mixed in 1,4-dioxane (8 mL) and water (4 mL) inmicrowave vial and charged with argon, the reaction mixture was heatedat 80 degree for 1 h. Reaction mixture was filtered and filtrate wasevaporated. The residue was purified with combi-flash column to affordethyl(1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropane-1-carboxylate.ES/MS m/z: 370.20.

Step 2. A suspension of ammonium chloride (0.45 g, 8.53 mmol) in Toluene(10 mL) was slowly mixed with 2M solution of trimethylaluminum (0.615 g,8.53 mmol) in toluene at 0 degree. After completion of gas evolution,the mixture was stirred at RT for 15 min. Then ethyl(1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropane-1-carboxylate(0.7 g, 1.9 mmol) was added and heated at 100 degree for 2 h. Quenchedthe reaction with MeOH. Filtered, washed with MeOH, evaporated solventand the residue was purified with Prep HPLC to afford(1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropane-1-carboximidamide.ES/MS m/z: 340.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 8.94 (s, 1H),8.73 (s, 1H), 8.24 (d, J=1.9 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.89 (s,2H), 7.65 (s, 1H), 4.09 (d, J=16.3 Hz, 6H), 3.46 (dd, J=9.8, 5.4 Hz,1H), 2.61 (dt, J=10.5, 5.6 Hz, 1H), 2.04 (dt, J=9.3, 6.2 Hz, 1H), 1.94(t, J=4.2 Hz, 1H).

Step 3. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.3 g, 2 mmol) was added to(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropanecarboxamidine(0.34 g, 1 mmol) solution in ACN (5 ml), the reaction mixture wasstirred at RT for 5 min, then 5-bromotriazine was added, the reactionmixture was heated at 80 degree for 1 h. The solvent was evaporated andthe residue was purified with combi-flash column to afford8-((1S,2S)-2-(5-bromopyrimidin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 454.10.

Step 4. A solution of8-((1S,2S)-2-(5-bromopyrimidin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(21 mg, 0.046 mmol) was dissolved in 1:1 1N HCl/MeOH (2 mL) was heatedto 80° C. for 1 h. The solvent was then evaporated and the residue waspurified with prep HPLC to afford5-[8-[(1S,2S)-2-(5-bromopyrimidin-2-yl)cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 426.00. ¹H NMR (400 MHz, DMSO-d6) δ 11.59 (dd, J=11.6, 4.2Hz, 2H), 8.93 (s, 2H), 8.43 (d, J=1.6 Hz, 1H), 8.06 (d, J=6.2 Hz, 1H),7.99 (s, 1H), 7.72 (s, 1H), 3.03 (ddt, J=10.2, 6.4, 3.3 Hz, 2H), 2.11(ddd, J=9.0, 7.1, 3.5 Hz, 1H), 1.93 (ddd, J=8.3, 6.2, 4.2 Hz, 1H).

Example 381.5-(3-fluoro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 527.20. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.21 (s, 2H),8.03 (d, J=6.3 Hz, 1H), 7.56 (s, 1H), 7.41 (d, J=6.8 Hz, 1H), 7.03-6.89(m, 3H), 4.51 (q, J=9.2 Hz, 2H), 2.79 (ddq, J=19.6, 9.9, 4.6 Hz, 2H),2.06 (dt, J=9.1, 5.5 Hz, 1H), 1.77 (dd, J=8.7, 5.5 Hz, 1H), 1.64 (t,J=4.1 Hz, 4H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −71.20 (t, J=9.2Hz), −77.29, −157.06 (d, J=6.8 Hz).

Example 382.5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemate)

5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 509.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.41(s, 1H), 9.29 (s, 1H), 8.18-8.10 (m, 2H), 7.96-7.88 (m, 2H), 7.08 (s,1H), 7.01 (dd, J=7.8, 1.5 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 4.56 (q,J=9.2 Hz, 2H), 3.04 (dt, J=9.3, 5.3 Hz, 1H), 2.76-2.66 (m, 1H),1.94-1.79 (m, 2H), 1.70-1.59 (m, 4H). ¹⁹F NMR (376 MHz, Acetonitrile-d3)δ −71.16 (t, J=9.1 Hz), −77.07.

Example 383.5-(8-((1S,2S)-2-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemate)

5-(8-((1S,2S)-2-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[1-[5-(trifluoromethyl)-2-pyridyl]indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemate). ES/MS m/z: 531.10. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d,J=4.8 Hz, 2H), 9.00 (d, J=2.3 Hz, 1H), 8.71 (s, 1H), 8.53 (s, 1H),8.41-8.33 (m, 2H), 8.18 (d, J=8.8 Hz, 1H), 8.09-8.02 (m, 1H), 7.90 (d,J=8.1 Hz, 2H), 7.64 (s, 1H), 7.31-7.24 (m, 1H), 3.05 (t, J=7.3 Hz, 1H),2.87 (dt, J=9.5, 5.1 Hz, 1H), 2.18 (dt, J=10.6, 5.5 Hz, 1H), 1.95 (dt,J=10.8, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −60.88, −75.17.

Example 384.5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one.ES/MS m/z: 523.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.31 (s, 1H),9.25 (s, 1H), 8.16-8.02 (m, 2H), 7.88 (d, J=1.8 Hz, 1H), 7.82 (s, 1H),7.55 (d, J=7.6 Hz, 1H), 7.07 (dd, J=7.7, 1.6 Hz, 1H), 6.91 (s, 1H),4.51-4.29 (m, 2H), 2.97-2.85 (m, 1H), 2.80-2.66 (m, 1H), 2.60-2.46 (m,2H), 2.45-2.17 (m, 4H), 1.90-1.73 (m, 2H). ¹⁹F NMR (376 MHz,Acetonitrile-d3) δ −71.20 (t, J=9.1 Hz), −76.96.

Example 385.5-(3-fluoro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one.ES/MS m/z: 555.20. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.18 (s, 2H),8.03 (d, J=6.3 Hz, 1H), 7.55 (s, 1H), 7.41 (d, J=6.8 Hz, 1H), 7.25 (d,J=7.7 Hz, 1H), 7.00 (dd, J=7.7, 1.5 Hz, 1H), 6.91 (s, 1H), 4.43 (q,J=9.2 Hz, 2H), 2.87-2.65 (m, 2H), 2.05 (ddt, J=13.1, 8.7, 4.5 Hz, 7H),1.90-1.83 (m, 2H), 1.83-1.65 (m, 1H). ¹⁹F NMR (376 MHz, Acetonitrile-d3)δ −71.20 (t, J=9.1 Hz), −77.30, −157.08 (d, J=6.9 Hz).

Example 386.5-(3-fluoro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclobutane-1,3′-indolin]-2′-one.ES/MS m/z: 541.20. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.19 (s, 2H),8.03 (d, J=6.4 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.41 (d, J=6.8 Hz, 1H),7.05 (dd, J=7.7, 1.5 Hz, 1H), 6.88 (s, 1H), 4.41 (q, J=9.2 Hz, 2H),2.87-2.68 (m, 2H), 2.62-2.46 (m, 2H), 2.47-2.17 (m, 4H), 2.07 (dt,J=8.9, 5.6 Hz, 1H), 1.86-1.69 (m, 1H). ¹⁹F NMR (376 MHz,Acetonitrile-d3) δ −71.20 (t, J=9.1 Hz), −77.29, −157.04 (d, J=6.8 Hz).

Example 387.5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopentane-1,3′-indolin]-2′-one.ES/MS m/z: 537.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.33 (s, 1H),9.26 (s, 1H), 8.16-8.07 (m, 2H), 7.93-7.83 (m, 2H), 7.25 (d, J=7.7 Hz,1H), 7.06-6.98 (m, 1H), 6.96 (s, 1H), 4.45 (q, J=9.2 Hz, 2H), 2.92-2.85(m, 1H), 2.69 (d, J=6.4 Hz, 1H), 2.04 (dd, J=6.1 Hz, 5H), 1.93-1.82 (m,5H). ¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −71.18 (t, J=9.2 Hz), −77.04.

Example 388.5-(3-chloro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Palau' Chlor (35 mg, 0.165 mmol) was added to solution of5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(84 mg, 0.165 mmol) in DMF at RT. The reaction mixture was stirred at RTfor 2 h and then purified with Prep HPLC to afford5-(3-chloro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 543.10. ¹H NMR (400 MHz, DMSO-d6) δ 11.58-11.50 (m, 2H), 8.04(d, J=6.1 Hz, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.18 (s, 1H), 7.03-6.93(m, 2H), 4.70 (q, J=9.4 Hz, 2H), 2.88 (ddd, J=9.0, 6.3, 4.3 Hz, 1H),2.74 (ddd, J=8.8, 5.9, 4.4 Hz, 1H), 2.11 (dt, J=8.9, 5.2 Hz, 1H),1.87-1.74 (m, 1H), 1.66 (q, J=4.0, 3.1 Hz, 2H), 1.58 (q, J=4.7, 3.8 Hz,2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −69.25 (t, J=9.4 Hz), −75.25.

Example 389.(S)-5-(8-(4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Added NaH (7.5 mg, 0.195 mmol) to(3S)-1-[6-(2,4-ditert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]-4,4-difluoro-pyrrolidin-3-431(30 mg, 0.065 mmol) in DMF (2 ml), stirred at RT for 10 mins, then tothe reaction mixture was added 4-(difluoromethyl)-2,5-difluoro-pyridine(21 mg, 0.12 mmol). The reaction mixture was stirred at 85 degree for 30mins and was then quenched with water and purified with Prep HPLC toafford(S)-5-(8-(4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 496.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.34 (d, J=24.1Hz, 2H), 8.23 (d, J=1.5 Hz, 1H), 8.12 (d, J=6.0 Hz, 1H), 8.05 (d, J=2.0Hz, 1H), 7.84 (s, 1H), 7.26 (s, 1H), 7.15-6.80 (m, 2H), 5.90 (q, J=7.9,5.8 Hz, 1H), 4.55-4.46 (m, 3H), 4.15 (dt, J=12.1, 2.7 Hz, 1H). ¹⁹F NMR(376 MHz, Acetonitrile-d3) δ −77.27 (d, J=4.7 Hz), −109.77 (d, J=240.3Hz), −119.60 (ddd, J=53.8, 40.3, 5.0 Hz), −122.22 (d, J=241.8 Hz),−144.87 (t, J=5.2 Hz).

Example 390.(S)-5-(8-(4-((4,5-difluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(4-((4,5-difluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 389, but replacing4-(difluoromethyl)-2,5-difluoro-pyridine with 2,4,5-trifluoropyridine.ES/MS m/z: 464.20. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.34 (d, J=14.9Hz, 2H), 8.15-8.07 (m, 1H), 8.05 (dd, J=4.2, 1.6 Hz, 2H), 7.83 (t, J=3.5Hz, 1H), 7.25 (s, 1H), 6.95 (dd, J=5.5, 1.3 Hz, 1H), 5.42 (tt, J=5.0,2.5 Hz, 1H), 4.56-4.35 (m, 3H), 4.35-4.17 (m, 1H). ¹⁹F NMR (376 MHz,Acetonitrile-d3) δ −70.42 (d, J=23.2 Hz), −77.23, −108.15 (dtd, J=243.9,20.3, 8.0 Hz), −120.09-−124.78 (m), −154.77 (ddd, J=23.1, 5.4, 2.7 Hz).

Example 391.5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas obtained through SFC chiral HPLC separation (peak 1) with racemic5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 509.10. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.27 (s, 1H),9.18 (s, 1H), 7.99 (d, J=9.3 Hz, 2H), 7.67 (s, 1H), 7.49 (s, 1H), 6.99(d, J=8.2 Hz, 2H), 6.92 (d, J=7.6 Hz, 1H), 4.50 (q, J=9.2 Hz, 2H),2.91-2.81 (m, 1H), 2.76 (dt, J=10.2, Hz, 1H), 2.11 (dt, J=8.9, 5.5 Hz,1H), 1.73 (dt, J=8.6, 5.5 Hz, 1H), 1.63 (t, J=3.8 Hz, 4H), 1.30 (s, 1H).¹⁹F NMR (376 MHz, Acetonitrile-d3) δ −71.19 (t, J=9.2 Hz)

Example 392.5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 486.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (dd, J=10.2,4.1 Hz, 2H), 9.27 (s, 1H), 8.35 (d, J=1.4 Hz, 1H), 8.13 (s, 1H), 8.05(d, J=6.1 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.85 (d, J=1.4 Hz, 1H), 7.68(s, 1H), 5.33 (q, J=8.9 Hz, 2H), 3.39 (dt, J=9.5, 5.5 Hz, 1H), 3.00(ddd, J=9.2, 6.2, 4.3 Hz, 1H), 2.35-2.26 (m, 1H), 2.14-2.04 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −70.74 (t, J=9.0 Hz), −75.24 (d, J=2.8 Hz).

Example 393.5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine.ES/MS m/z: 486.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65 (dd, J=34.2,4.1 Hz, 2H), 8.51 (s, 1H), 8.17-8.08 (m, 2H), 7.89-7.66 (m, 3H), 7.21(dd, J=8.5, 1.2 Hz, 1H), 5.34 (q, J=9.0 Hz, 2H), 3.07-2.90 (m, 2H),2.09-1.93 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.24 (t, J=9.0 Hz),−133.85.

Example 394.5-(8-((1S,2S)-2-(5-(trifluoromethyl)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(trifluoromethyl)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-5-(trifluoromethyl)quinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.60 (d, J=10.1Hz, 2H), 9.06 (dd, J=4.3, 1.5 Hz, 1H), 8.51-8.40 (m, 2H), 8.21 (s, 1H),8.08 (d, J=6.1 Hz, 1H), 8.06-7.97 (m, 2H), 7.76-7.67 (m, 2H), 3.15 (dt,J=9.7, 5.6 Hz, 1H), 3.00 (dt, J=9.6, 5.4 Hz, 1H), 2.20 (dt, J=9.9, 5.7Hz, 1H), 2.10 (dt, J=8.7, 5.7 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−58.50, −75.27 (d, J=4.6 Hz).

Example 395.5-(8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(8-(trifluoromethyl)quinolin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-8-(trifluoromethyl)quinoline.ES/MS m/z: 465.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.64-11.56 (m,2H), 9.05 (d, J=2.3 Hz, 1H), 8.40 (dd, J=16.9, 2.0 Hz, 2H), 8.28-8.21(m, 1H), 8.11 (dd, J=25.4, 6.7 Hz, 2H), 7.98 (s, 1H), 7.80-7.71 (m, 2H),3.06 (dt, J=9.4, 5.6 Hz, 1H), 3.01-2.91 (m, 1H), 2.24 (dt, J=9.3, 5.5Hz, 1H), 2.07 (dt, J=8.5, 5.5 Hz, 1H).

Example 396.5-(8-((1S,2S)-2-(3-isopropyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-isopropyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-[(1S,2S)-2-[3-isopropyl-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazine(racemic).ES/MS m/z: 510.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d, J=4.9 Hz,2H), 8.35 (d, J=1.5 Hz, 1H), 8.04 (d, J=6.3 Hz, 1H), 7.88 (s, 1H), 7.77(d, J=8.4 Hz, 1H), 7.62 (d, J=16.2 Hz, 2H), 7.07 (dd, J=8.4, 1.4 Hz,1H), 5.31 (q, J=9.1 Hz, 2H), 3.35 (h, J=6.9 Hz, 1H), 2.98 (ddd, J=9.2,6.3, 4.3 Hz, 1H), 2.84-2.75 (m, 1H), 2.11 (dq, J=12.5, 4.5, 3.7 Hz, 1H),1.97-1.87 (m, 1H), 1.37 (d, J=7.0 Hz, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−69.99 (t, J=9.1 Hz), −75.16.

Example 397.5-(8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 371.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.51-11.34(m, 2H), 8.10 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.60 (d, J=1.2Hz, 1H), 6.61 (s, 1H), 4.93-4.71 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.26, −82.92 (d, J=7.5 Hz), −172.25-−172.66 (m).

Example 398.5-(8-(2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-imidazol-1-yl-imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 325.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.39 (d,J=7.6 Hz, 2H), 8.08 (s, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.66 (s, 1H), 6.52(s, 1H), 4.34 (s, 4H), 2.23 (t, J=7.6 Hz, 4H), 1.82 (p, J=7.6 Hz, 2H).

Example 399.5-(8-(3-(difluoromethyl)-3-methylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(difluoromethyl)-3-methylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-(difluoromethyl)-3-methylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 349.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53-11.22(m, 2H), 8.04 (d, J=1.3 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.57 (d, J=1.2Hz, 1H), 6.48 (s, 1H), 6.33 (t, J=56.4 Hz, 1H), 4.38 (br s, 2H), 4.11(br s, 2H), 1.41 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.21 (d, J=2.9Hz), −129.98 (d, J=56.3 Hz).

Example 400.5-(8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-(2,2-difluorocyclopropyl)azetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 361.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.47-11.32(m, 2H), 8.05 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.60 (d, J=1.2Hz, 1H), 6.49 (s, 1H), 4.52 (br s, 2H), 4.19 (br s, 2H), 2.84 (h, J=7.6Hz, 1H), 2.22 (tt, J=11.4, 7.9 Hz, 1H), 1.63 (tdd, J=12.3, 7.9, 4.5 Hz,1H), 1.37 (dtd, J=11.5, 7.7, 3.6 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.19, −126.51-−127.27 (m), —141.33-−142.11 (m).

Example 401.5-(8-(3-cyclobutylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-cyclobutylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-cyclobutylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 339.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.31(m, 2H), 8.03 (s, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.57 (s, 1H), 6.45 (s,1H), 4.40 (br s, 2H), 3.99 (br s, 2H), 2.87 (dq, J=11.0, 4.1, 2.9 Hz,1H), 2.66 (p, J=8.0 Hz, 1H), 2.04 (ddd, J=14.2, 6.1 Hz, 2H), 1.85 (tdd,J=18.9, 9.5, 4.6 Hz, 2H), 1.77-1.65 (m, 2H).

Example 402.5-(7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(2,4-dimethoxypyrimidin-5-yl)-7-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 372.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.72-11.57(m, 1H), 11.51 (s, 1H), 8.47 (d, J=6.4 Hz, 1H), 8.42 (s, 1H), 7.33 (s,1H), 4.98 (dq, J=22.9, 11.7 Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−74.13, −82.62 (d, J=7.7 Hz), −172.61.

Example 403.5-(8-(3-(difluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(difluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-(difluoromethyl)azetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine,and running the reaction at 70° C. for 3 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 335.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.46-11.29(m, 2H), 8.03 (s, 1H), 7.92 (d, J=6.0 Hz, 1H), 7.56 (s, 1H), 6.46 (s,1H), 6.43 (t, J=56.3, 4.3 Hz, 1H), 4.48 (br s, 2H), 4.30 (br s, 2H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −75.05, −125.00 (dd, J=56.4, 14.8 Hz).

Example 404.5-(8-(3-cyclopropylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-cyclopropylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-cyclopropylazetidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 325.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.52-11.30(m, 2H), 8.05 (d, J=4.4 Hz, 1H), 7.94 (d, J=5.8 Hz, 1H), 7.61 (s, 1H),6.47 (d, J=4.4 Hz, 1H), 4.42 (br s, 2H), 4.01 (br s, 2H), 1.24-0.98 (m,1H), 0.50 (d, J=7.7 Hz, 2H), 0.22 (d, J=5.0 Hz, 2H).

Example 405.5-(8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(5,5-difluoro-2-azaspiro[3.3]heptan-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 361.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.50-11.28(m, 2H), 8.06 (d, J=1.3 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.60 (d, J=1.3Hz, 1H), 6.53 (s, 1H), 4.55 (d, J=9.9 Hz, 2H), 4.33 (d, J=9.7 Hz, 2H),2.60-2.51 (m, 2H), 2.17-2.07 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.25, −101.34.

Example 406.5-(8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(1,1-difluoro-5-azaspiro[2.3]hexan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 347.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.48-11.33(m, 2H), 8.06 (s, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.59 (s, 1H), 6.55 (s,1H), 4.51 (s, 4H), 1.84 (t, J=8.9 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.22, −138.15 (t, J=9.5 Hz).

Example 407.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3-fluorobenzonitrile,and running the reaction at 70° C. for 3 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 389.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d,J=5.5 Hz, 2H), 8.35 (d, J=1.5 Hz, 1H), 8.03 (d, J=6.1 Hz, 1H), 7.93-7.86(m, 1H), 7.83 (dd, J=10.2, 1.6 Hz, 1H), 7.71 (dd, J=8.0, 1.6 Hz, 1H),7.65 (s, 1H), 7.49 (t, J=7.9 Hz, 1H), 3.09-3.00 (m, 1H), 2.86 (ddd,J=8.9, 6.1, 4.5 Hz, 1H), 2.18 (dt, J=8.9, 5.3 Hz, 1H), 1.91 (ddd, J=8.9,6.3, 4.8 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.21, −117.94 (t, J=8.9Hz).

Example 408.3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile,and running the reaction at 70° C. for 3 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 389.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d,J=5.9 Hz, 2H), 8.36 (d, J=1.4 Hz, 1H), 8.03 (d, J=6.1 Hz, 1H), 7.91 (s,1H), 7.80 (ddd, J=7.8, 6.1, 1.7 Hz, 1H), 7.71-7.63 (m, 2H), 7.41 (t,J=7.8 Hz, 1H), 3.01 (dt, J=9.1, 5.6 Hz, 1H), 2.85-2.77 (m, 1H), 2.13(dt, J=8.9, 5.3 Hz, 1H), 1.92-1.84 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.19, −115.20.

Example 409.5-(8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(2-fluoropropan-2-yl)azetidin-1-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 345.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.46-11.28(m, 2H), 8.03 (s, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.56 (s, 1H), 6.45 (s,1H), 4.41 (br s, 2H), 4.24 (br s, 2H), 3.14-2.95 (m, 1H), 1.36 (s, 3H),1.31 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.07, −152.62-−153.15 (m).

Example 410.5-(8-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(tetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 314.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.81 (dd,J=6.5, 2.0 Hz, 1H), 11.63 (d, J=1.9 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H),8.27 (d, J=1.9 Hz, 1H), 8.14 (d, J=6.3 Hz, 1H), 8.09 (s, 1H), 4.11-3.93(m, 2H), 3.64-3.47 (m, 3H), 1.91 (ddd, J=12.4, 4.0, 1.8 Hz, 2H), 1.77(qd, J=12.2, 4.3 Hz, 2H).

Example 411.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile,and running the reaction at 70° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 439.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d,J=7.6 Hz, 2H), 8.35 (d, J=1.4 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 8.04 (d,J=6.1 Hz, 1H), 7.90 (dd, J=7.9, 1.5 Hz, 2H), 7.78 (dd, J=8.1, 1.7 Hz,1H), 7.64 (s, 1H), 3.06 (ddd, J=9.1, 6.1, 4.3 Hz, 1H), 2.92 (ddd, J=9.0,6.1, 4.3 Hz, 1H), 2.24 (dt, J=8.8, 5.5 Hz, 1H), 1.99 (dt, J=8.8, 5.5 Hz,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −61.15, −75.21.

Example 412.5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile

5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzonitrile,and running the reaction at 70° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 439.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s,2H), 8.31 (s, 1H), 8.09 (d, J=1.6 Hz, 1H), 8.02 (d, J=6.4 Hz, 1H), 7.93(d, J=8.4 Hz, 1H), 7.88-7.78 (m, 2H), 7.60 (s, 1H), 3.07-3.00 (m, 1H),2.90 (ddd, J=8.9, 6.2, 4.4 Hz, 1H), 2.25 (dt, J=8.8, 5.4 Hz, 1H), 1.94(dt, J=8.8, 5.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −60.80, −75.02.

Example 413.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile,and running the reaction at 70° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 455.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d,J=6.6 Hz, 2H), 8.35 (d, J=1.4 Hz, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.99 (d,J=8.1 Hz, 1H), 7.92-7.83 (m, 1H), 7.68-7.58 (m, 2H), 7.51 (dd, J=8.2,1.6 Hz, 1H), 3.03 (ddd, J=9.0, 6.2, 4.3 Hz, 1H), 2.89 (ddd, J=9.0, 6.3,4.3 Hz, 1H), 2.22 (dt, J=9.0, 5.6 Hz, 1H), 1.92 (dt, J=8.8, 5.4 Hz, 1H).¹⁹F NMR (376 MHz, DMSO-d6) δ −57.52, −75.23.

Example 414.5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile

5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile(racemic mixture) was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethoxy)benzonitrile,and running the reaction at 70° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 455.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.69-11.45(m, 2H), 8.37 (d, J=1.5 Hz, 1H), 8.05 (d, J=6.1 Hz, 1H), 7.97 (d, J=2.4Hz, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.79 (dd, J=8.8, 2.4 Hz, 1H), 7.64 (d,J=7.2 Hz, 2H), 2.93 (ddd, J=9.0, 6.2, 4.3 Hz, 1H), 2.84 (ddd, J=8.9,6.1, 4.4 Hz, 1H), 2.15 (dt, J=8.8, 5.5 Hz, 1H), 1.90 (dt, J=8.8, 5.5 Hz,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −57.81, −75.22.

Example 415.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile,and running the reaction at 70° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 407.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (d,J=4.2 Hz, 2H), 8.02 (d, J=6.4 Hz, 1H), 7.84 (dd, J=8.1, 7.1 Hz, 1H),7.55 (d, J=7.1 Hz, 1H), 7.52 (s, 1H), 7.48 (dd, J=11.1, 1.6 Hz, 1H),7.34 (dd, J=8.1, 1.6 Hz, 1H), 2.99 (dt, J=9.4, 5.4 Hz, 1H), 2.83 (ddd,J=8.9, 6.2, 4.3 Hz, 1H), 2.27 (ddd, J=8.8, 6.2, 4.9 Hz, 1H), 1.87 (dt,J=8.8, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.24, −109.46 (dd,J=11.1, 7.0 Hz), −155.57 (d, J=7.0 Hz).

Example 416.5-(7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine,and running the reaction at 70° C. for 3 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 383.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.76 (d,J=6.2 Hz, 1H), 11.59 (d, J=1.9 Hz, 1H), 8.61 (s, 1H), 8.50 (d, J=6.4 Hz,1H), 8.04 (s, 1H), 7.45 (td, J=8.8, 6.4 Hz, 1H), 7.25 (ddd, J=10.7, 9.2,2.6 Hz, 1H), 7.10 (td, J=8.6, 2.5 Hz, 1H), 2.99 (dt, J=8.9, 5.6 Hz, 1H),2.79 (dt, J=9.3, 6.0 Hz, 1H), 1.92 (ddt, J=23.8, 8.7, 5.6 Hz, 2H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −112.84 (ddd, J=15.4, 8.6, 6.4 Hz), −115.28(td, J=9.9, 7.1 Hz).

Example 417.5-(7-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(2,4-dimethoxypyrimidin-5-yl)-7-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrimidine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 415.1 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.72 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H), 7.65 (d, J=8.2Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 3.30-3.23 (m, 2H), 2.95-2.81 (m, 1H),2.18-2.05 (m, 1H), 2.00-1.90 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−64.48, −77.54.

Example 418.5-(8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 396.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.56 (d, J=6.3 Hz, 2H), 8.35 (d, J=1.5 Hz, 1H), 8.03 (d,J=6.1 Hz, 1H), 7.92-7.86 (m, 1H), 7.60 (s, 1H), 7.52 (d, J=8.0 Hz, 2H),7.40 (d, J=8.0 Hz, 2H), 7.01 (t, J=56.0 Hz, 1H), 2.86 (ddd, J=9.0, 6.3,4.4 Hz, 1H), 2.79 (ddd, J=8.8, 6.0, 4.4 Hz, 1H), 2.12-2.04 (m, 1H), 1.82(ddd, J=8.7, 6.3, 4.9 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.13,−109.27 (d, J=56.1 Hz).

Example 419.5-(8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-(difluoromethyl)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 414.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.53 (d, J=3.1 Hz, 2H), 8.02 (d, J=6.3 Hz, 1H), 7.54 (d,J=7.0 Hz, 1H), 7.53-7.45 (m, 3H), 7.39 (d, J=8.0 Hz, 2H), 7.00 (t,J=56.0 Hz, 1H), 2.89 (dt, J=9.4, 5.6 Hz, 1H), 2.78-2.69 (m, 1H), 2.13(dt, J=8.8, 5.3 Hz, 1H), 1.79 (dq, J=12.9, 4.9, 4.4 Hz, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.47, −109.28 (d, J=56.1 Hz), —155.56 (d, J=7.0Hz).

Example 420.5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidine,and running the reaction at 60° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 364.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62 (d,J=6.5 Hz, 1H), 11.50 (d, J=1.9 Hz, 1H), 8.47 (d, J=6.4 Hz, 1H), 8.37 (s,1H), 7.39 (s, 1H), 4.56 (t, J=13.5 Hz, 2H), 3.89 (s, 2H), 1.22 (s, 6H).¹⁹F NMR (376 MHz, DMSO-d6) δ −74.24, −115.21 (t, J=13.6 Hz).

Example 421.5-(5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-a]pyrimidin-7-yl)pyrimidine-2,4(1H,3H)-dione

5-(5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-a]pyrimidin-7-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-7-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-a]pyrimidine,and running the reaction at 70° C. for 2 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 363.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 12.03-11.81(m, 1H), 11.64 (s, 1H), 8.47 (d, J=4.8 Hz, 1H), 8.23 (d, J=2.8 Hz, 1H),8.01 (d, J=2.7 Hz, 1H), 7.67 (s, 1H), 4.58 (t, J=13.1 Hz, 2H), 3.82 (s,2H), 1.24 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.15, −115.51 (t,J=13.2 Hz).

Example 422.5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoro-2-methylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-2-methylimidazo[1,2-b]pyridazine,and running the reaction for 16 h. Purification was accomplished byRP-HPLC (10-90% MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z:395.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.42 (d, J=2.0 Hz, 1H), 11.38(dd, J=6.1, 2.1 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 6.55 (s, 1H), 4.37 (brs, 2H), 3.83 (br s, 2H), 2.32 (s, 3H), 1.20 (s, 6H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.17, −115.45, −158.59.

Example 423.5-(8-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-(hydroxymethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methanol,and running the reaction at 70° C. for 16 h. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 333.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.35(m, 2H), 8.08 (d, J=1.3 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.61 (d, J=1.2Hz, 1H), 6.55 (s, 1H), 4.52 (d, J=15.6 Hz, 2H), 4.39 (dd, J=20.6, Hz,2H), 3.80-3.72 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.32, −157.16(tt, J=21.0, 18.4 Hz).

Example 424.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 407.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.55 (d, J=5.7 Hz, 2H), 8.35 (d, J=1.4 Hz, 1H), 8.03 (d,J=6.1 Hz, 1H), 7.87 (s, 1H), 7.82-7.77 (m, 2H), 7.66 (s, 1H), 3.02 (dt,J=8.9, 5.6 Hz, 1H), 2.95 (ddd, J=9.3, 6.6, 4.9 Hz, 1H), 2.16 (dt,J=10.2, 5.5 Hz, 1H), 1.95 (ddd, J=8.8, 6.6, 4.8 Hz, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −75.17, −112.26 (d, J=8.2 Hz).

Example 425.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 425.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.54 (d, J=4.6 Hz, 2H), 8.03 (d, J=6.3 Hz, 1H), 7.82-7.75(m, 2H), 7.58-7.52 (m, 2H), 3.04-2.95 (m, 2H), 2.19 (dt, J=9.9, 5.3 Hz,1H), 1.92 (ddd, J=8.9, 6.6, 4.7 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.38, −112.20 (d, J=7.6 Hz), −155.57 (d, J=7.1 Hz).

Example 426.5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 364.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.47 (d, J=5.4 Hz, 2H), 8.44 (s, 1H), 8.05 (d, J=5.3 Hz,1H), 6.98 (s, 1H), 4.39 (br s, 2H), 3.86 (br s, 2H), 1.21 (s, 6H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −115.17.

Example 427.5-(8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 415.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.60 (d, J=7.9 Hz, 2H), 8.61 (s, 1H), 8.12 (d, J=6.1 Hz,1H), 7.97 (s, 1H), 7.67 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 3.03(ddd, J=9.1, 6.2, 4.4 Hz, 1H), 2.80 (ddd, J=9.0, 6.0, 4.4 Hz, 1H), 2.25(dt, J=8.9, 5.3 Hz, 1H), 1.87 (dt, J=8.7, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −61.26.

Example 428.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)cyclopropyl)-3,5-difluorobenzonitrile.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 408.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.59 (d, J=10.2 Hz, 2H), 8.62 (s, 1H), 8.12 (d, J=6.1 Hz,1H), 8.03 (s, 1H), 7.80 (d, J=7.2 Hz, 2H), 3.02 (ddt, J=13.4, 8.8, 5.4Hz, 2H), 2.23 (dt, J=10.4, 5.2 Hz, 1H), 2.00-1.90 (m, 1H). ¹⁹F NMR (376MHz, DMSO-d6) δ −112.04 (d, J=7.6 Hz).

Example 429.(R)-5-(8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(R)-6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(trifluoromethoxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 384.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.45 (d, J=6.7 Hz, 2H), 8.42 (s, 1H), 8.05 (d, J=6.0 Hz,1H), 6.99 (s, 1H), 5.32 (dq, J=6.0, 3.6, 2.9 Hz, 1H), 4.13 (br s, 1H),3.79 (br s, 1H), 3.42-3.25 (m, 2H), 2.44-2.27 (m, 2H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −57.32.

Example 430.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-5-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 469.2 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.65-11.49 (m, 2H), 8.60 (s, 1H), 8.14 (d, J=0.9 Hz, 1H),8.11 (d, J=6.1 Hz, 1H), 7.93 (s, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.69 (d,J=1.5 Hz, 1H), 7.40 (dd, J=8.8, 1.7 Hz, 1H), 5.43 (q, J=9.1 Hz, 2H),3.03 (ddd, J=9.1, 6.4, 4.4 Hz, 1H), 2.73 (ddd, J=8.7, 5.8, 4.4 Hz, 1H),2.17 (dt, J=9.0, 5.2 Hz, 1H), 1.86 (ddd, J=8.8, 6.5, 4.9 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −70.16 (t, J=9.2 Hz).

Example 431.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 469.2 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.67-11.47 (m, 2H), 8.61 (s, 1H), 8.15 (d, J=0.8 Hz, 1H),8.12 (d, J=6.1 Hz, 1H), 7.96 (s, 1H), 7.76-7.70 (m, 2H), 7.13 (dd,J=8.5, 1.2 Hz, 1H), 5.40 (q, J=9.2 Hz, 2H), 3.09 (ddd, J=9.0, 6.3, 4.4Hz, 1H), 2.79 (ddd, J=8.8, 5.8, 4.3 Hz, 1H), 2.23 (dt, J=8.9, 5.2 Hz,1H), 1.92 (ddd, J=8.8, 6.4, 4.8 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−70.08 (t, J=9.1 Hz).

Example 432.5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 497.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.48 (d, J=4.7 Hz, 2H), 8.70 (dt, J=2.1, 1.0 Hz, 1H), 8.46(s, 1H), 8.19 (dd, J=8.7, 2.6 Hz, 1H), 8.06 (d, J=6.3 Hz, 1H), 7.20 (d,J=8.8 Hz, 1H), 7.04 (s, 1H), 6.04 (t, J=4.3 Hz, 1H), 4.73-4.35 (m, 3H),4.20 (s, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −60.56, −108.00 (d, J=241.1Hz), −119.20 (d, J=238.2 Hz).

Example 433.5-(8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 372.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.50 (s, 2H), 8.48 (s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.00 (s,1H), 4.86 (dq, J=25.4, 11.8 Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −82.83(d, J=7.6 Hz), −172.26-−172.72 (m).

Example 434.5-(8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(trifluoromethyl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)azetidin-1-yl)imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 514.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.47-11.33 (m, 2H), 8.65 (d, J=2.4 Hz, 1H), 8.22 (dd, J=8.8,2.6 Hz, 1H), 8.09 (d, J=1.3 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.61 (d,J=1.3 Hz, 1H), 7.24 (d, J=8.7 Hz, 1H), 6.63 (s, 1H), 4.94 (br s, 4H).¹⁹F NMR (376 MHz, DMSO-d6) δ −60.70, −75.39, −78.68.

Example 435.5-(8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-fluoro-3-(((5-(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidin-1-yl)imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 478.2 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.49-11.29 (m, 2H), 8.61 (s, 1H), 8.12 (dd, J=8.8, 2.5 Hz,1H), 8.07 (s, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.60 (s, 1H), 7.13 (d, J=8.7Hz, 1H), 6.58 (s, 1H), 4.87 (d, J=23.1 Hz, 2H), 4.69 (d, J=17.2 Hz, 2H),4.54 (dd, J=21.4, 10.7 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −60.47,−75.32, −155.75 (dt, J=42.3, 21.3 Hz).

Example 436.1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate

1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate was prepared as a racemic mixture in themanner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith1-(6-(2,4-dimethoxypyrimidin-5-yl)[1,2,4]triazolo[1,5-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate. Purification was accomplished byRP-HPLC (10-90% MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z:477.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.50 (d, J=6.7 Hz, 2H), 8.48(s, 1H), 8.45 (t, J=6.4 Hz, 1H), 8.06 (d, J=6.0 Hz, 1H), 7.03 (s, 1H),5.55 (s, 1H), 4.64-3.95 (m, 4H), 3.95-3.75 (m, 2H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −71.98 (t, J=9.5 Hz), −108.32 (d, J=251.2 Hz), −119.76 (d,J=243.5 Hz).

Example 437.(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate

(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate was prepared in the manner described forExample 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-fluoroazetidin-3-yl)methyl(2,2,2-trifluoroethyl)carbamate. Purification was accomplished byRP-HPLC (10-90% MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z:458.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.48-11.26 (m, 2H), 8.22 (t,J=6.5 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.58 (d,J=1.2 Hz, 1H), 6.54 (s, 1H), 4.70-4.36 (m, 6H), 3.82 (qd, J=9.6, 6.3 Hz,2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −72.03 (t, J=9.6 Hz), −75.21, −156.20(p, J=20.9 Hz).

Example 438.3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate

3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate was prepared in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-((6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate. Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 426.1 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.73-11.51 (m, 2H), 8.59 (s, 1H), 8.15 (d,J=6.2 Hz, 1H), 7.77 (s, 1H), 7.42 (d, J=7.7 Hz, 1H), 4.87 (t, J=12.9 Hz,2H), 4.49 (t, J=14.1 Hz, 2H), 3.57 (dq, J=13.4, 6.7 Hz, 1H), 1.04 (d,J=6.5 Hz, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −113.57 (p, J=13.6 Hz).

Example 439.5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 382.0 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.59 (d, J=7.3 Hz, 2H), 8.60 (s, 1H), 8.56 (d, J=2.5 Hz,1H), 8.11 (d, J=6.1 Hz, 1H), 7.94 (s, 1H), 7.84 (dd, J=8.4, 2.5 Hz, 1H),7.51 (d, J=8.3 Hz, 1H), 3.12 (ddd, J=8.8, 5.9, 4.1 Hz, 1H), 2.96-2.88(m, 1H), 2.17 (ddd, J=8.7, 6.0, 4.0 Hz, 1H), 1.88 (ddd, J=9.6, 5.9, 4.0Hz, 1H).

Example 440.5-(2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a mixture of2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(60 mg, 0.134 mmol) in MeCN (3 mL) was added iodotrimethylsilane (0.19mL, 1.34 mmol). The mixture was stirred at rt for 45 min, after which itwas concentrated in vacuo and the resulting residue purified by RP-HPLC(10-90% MeCN/H₂O with TFA modifier, Gemini column) to afford5-(2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 421.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41 (d, J=2.0 Hz,1H), 11.37 (dd, J=6.2, 2.0 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 6.55 (s,1H), 4.38 (br s, 2H), 3.76 (br s, 2H), 2.02 (tt, J=8.3, 5.0 Hz, 1H),1.19 (s, 6H), 0.95 (dt, J=8.3, 2.8 Hz, 2H), 0.92-0.84 (m, 2H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.28, −115.44 (t, J=13.9 Hz), −159.35.

Example 441.5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 440, but replacing2-cyclopropyl-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-(1-(trifluoromethyl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 471.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.41 (d, J=2.0 Hz, 1H), 11.38 (dd, J=6.2, 2.0 Hz, 1H), 8.03(s, 1H), 7.93 (d, J=6.1 Hz, 1H), 6.60 (s, 1H), 4.42 (br s, 2H), 3.76 (brs, 2H), 1.40 (t, J=3.8 Hz, 4H), 1.20 (s, 6H). ¹⁹F NMR (376 MHz, DMSO-d6)δ −68.12, −75.41, −115.39 (t, J=13.8 Hz).

Example 442.5-(8-(6-azabicyclo[3.2.0]heptan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(6-azabicyclo[3.2.0]heptan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.162 mmol) in NMP (1 mL) was added DIPEA (0.034 mL, 0.195 mmol),followed by 6-azabicyclo[3.2.0]heptane (0.018 mL, 0.179 mmol). The vialwas sealed and heated to 130° C. for 4 h, after which more6-azabicyclo[3.2.0]heptane (0.018 mL, 0.179 mmol) was added. The mixturewas heated to 130° C. for 2 h, then cooled to rt. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn) to afford5-(8-(6-azabicyclo[3.2.0]heptan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 325.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.36 (d, J=2.1 Hz,1H), 11.33 (d, J=6.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=6.1 Hz, 1H), 7.55(s, 1H), 6.41 (s, 1H), 5.07 (br s, 1H), 4.36 (br s, 1H), 3.13 (q,J=10.8, 8.7 Hz, 1H), 2.23 (d, J=13.4 Hz, 1H), 1.89-1.74 (m, 4H), 1.55(q, J=10.9, 9.3 Hz, 2H).

Example 443.5-(8-(3-(2,2-difluoroethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2,2-difluoroethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3-(2,2-difluoroethyl)azetidine,2,2,2-trifluoroacetate. Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 349.1 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.38 (d, J=2.1 Hz, 1H), 11.35 (d, J=6.8 Hz,1H), 8.00 (d, J=1.2 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.54 (d, J=1.2 Hz,1H), 6.43 (s, 1H), 6.33-5.97 (m, 1H), 4.49 (br s, 2H), 4.11 (br s, 2H),3.08-2.97 (m, 1H), 2.30-2.21 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−74.87, −116.56 (dt, J=56.1, 18.3 Hz).

Example 444.5-(8-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2,2-difluoroethyl)-3-methylazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3-(2,2-difluoroethyl)-3-methyl-azetidinehydrochloride. Purification was accomplished by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier, Gemini column). ES/MS m/z: 363.1 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.46-11.23 (m, 2H), 8.03 (d, J=1.3 Hz, 1H), 7.93 (d,J=6.1 Hz, 1H), 7.57 (d, J=1.3 Hz, 1H), 6.47 (s, 1H), 6.26 (tt, J=55.8,4.8 Hz, 1H), 4.23 (br s, 2H), 4.05 (br s, 2H), 2.28 (td, J=18.0, 4.7 Hz,2H), 1.43 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.15, −114.55 (dt,J=56.0, 17.9 Hz).

Example 445.5-(8-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-methyl-3-(2,2,2-trifluoroethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with3-methyl-3-(2,2,2-trifluoroethyl)azetidine hydrochloride. Purificationwas accomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 381.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.39 (d,J=2.0 Hz, 1H), 11.38-11.31 (m, 1H), 8.03 (d, J=1.2 Hz, 1H), 7.93 (d,J=6.1 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 6.47 (s, 1H), 4.27 (br s, 2H),4.09 (br s, 2H), 2.80 (q, J=12.0 Hz, 2H), 1.47 (s, 3H). ¹⁹F NMR (376MHz, DMSO-d6) δ −60.86 (t, J=11.9 Hz), −75.09.

Example 446.5-(8-(3-(bicyclo[1.1.1]pentan-1-yl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(bicyclo[1.1.1]pentan-1-yl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3-(1-bicyclo[1.1.1]pentanyl)azetidine,2,2,2-trifluoroacetate. Purification was accomplished by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 351.1 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.42-11.33 (m, 2H), 8.04 (d, J=1.3 Hz, 1H),7.93 (d, J=6.1 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 6.46 (s, 1H), 4.36 (brs, 2H), 4.06 (br s, 2H), 2.87 (ddt, J=10.8, 8.2, 4.2 Hz, 1H), 1.80-1.68(m, 7H).

Example 447.5-(8-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3-(2,2,2-trifluoroethoxy)azetidinehydrochloride. Purification was accomplished by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier, Gemini column). ES/MS m/z: 383.1 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.40 (d, J=7.5 Hz, 2H), 8.05 (d, J=1.3 Hz, 1H), 7.94(d, J=5.9 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 6.50 (s, 1H), 4.69 (tt,J=6.6, 3.7 Hz, 1H), 4.60 (t, J=8.1 Hz, 2H), 4.28-4.13 (m, 4H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −73.39 (t, J=9.3 Hz), −75.09.

Example 448.5-(8-(6-(difluoromethyl)-2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(6-(difluoromethyl)-2-azaspiro[3.3]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with6-(difluoromethyl)-2-azaspiro[3.3]heptane hydrochloride. Purificationwas accomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 375.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (d,J=2.0 Hz, 1H), 11.36 (dd, J=6.2, 2.0 Hz, 1H), 8.01 (d, J=1.2 Hz, 1H),7.92 (d, J=6.1 Hz, 1H), 7.55 (d, J=1.2 Hz, 1H), 6.43 (s, 1H), 6.08 (td,J=57.2, 4.1 Hz, 1H), 4.34 (br d, J=36.5 Hz, 4H), 2.74-2.62 (m, 1H),2.42-2.34 (m, 2H), 2.30-2.19 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−74.94, −123.55 (dd, J=57.1, 16.1 Hz).

Example 449.5-(8-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7,7-difluoro-5-oxa-2-azaspiro[3.4]octan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with7,7-difluoro-5-oxa-2-azaspiro[3.4]octane, 2,2,2-trifluoroacetate.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 377.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.44-11.32 (m, 2H), 8.05 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 6.51 (s, 1H), 4.56 (br s, 2H), 4.40 (d,J=10.0 Hz, 2H), 4.10 (t, J=13.1 Hz, 2H), 2.87 (t, J=14.4 Hz, 2H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −75.21, −100.84 (p, J=13.7 Hz).

Example 450.5-(8-(3-(2,4-difluorobenzyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2,4-difluorobenzyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3-[(2,4-difluorophenyl)methyl]azetidine,hydrochloride. Purification was accomplished by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier, Gemini column). ES/MS m/z: 411.1 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.43-11.32 (m, 2H), 8.05 (d, J=1.3 Hz, 1H), 7.93 (d,J=6.0 Hz, 1H), 7.59 (s, 1H), 7.43 (td, J=8.7, 6.6 Hz, 1H), 7.22 (td,J=9.9, 2.6 Hz, 1H), 7.05 (td, J=8.5, 2.6 Hz, 1H), 6.48 (s, 1H), 4.43 (brs, 2H), 4.08 (br s, 2H), 3.09 (h, J=6.9 Hz, 1H), 3.00 (d, J=7.8 Hz, 2H).¹⁹F NMR (376 MHz, DMSO-d6) δ −75.22, −113.33 (ddd, J=15.7, 8.8, 6.7 Hz),−114.36 (q, J=8.5 Hz).

Example 451.5-(8-(7-azabicyclo[4.2.0]octan-7-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7-azabicyclo[4.2.0]octan-7-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 7-azabicyclo[4.2.0]octane. Purificationwas accomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 339.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (d,J=5.3 Hz, 2H), 8.05 (d, J=1.3 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.61 (d,J=1.3 Hz, 1H), 6.63 (s, 1H), 4.73-4.62 (m, 1H), 4.29 (t, J=8.6 Hz, 1H),4.18-4.12 (m, 1H), 2.91-2.80 (m, 1H), 2.06-1.85 (m, 2H), 1.85-1.51 (m,4H), 1.51-1.34 (m, 2H).

Example 452.5-(8-(3-(2,2,2-trifluoroethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2,2,2-trifluoroethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example442, but replacing 6-azabicyclo[3.2.0]heptane with3-(2,2,2-trifluoroethyl)pyrrolidine hydrochloride. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 381.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.47-11.19(m, 2H), 8.02 (s, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.55 (s, 1H), 6.58 (s,1H), 3.69 (br s, 2H), 3.50 (br s, 2H), 2.57 (m, 3H), 2.28-2.15 (m, 1H),1.78 (t, J=10.6 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −63.82 (t, J=11.3Hz), −75.16 (d, J=3.3 Hz).

Example 453.5-(8-(3-(2,2-difluoroethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(2,2-difluoroethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example442, but replacing 6-azabicyclo[3.2.0]heptane with3-(2,2-difluoroethyl)pyrrolidine hydrochloride. Purification wasaccomplished by RP-HPLC (10-90% MeCN/H₂O with TFA modifier, Geminicolumn). ES/MS m/z: 363.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.48-11.23(m, 2H), 8.04 (d, J=1.2 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.2Hz, 1H), 6.59 (s, 1H), 6.21 (tt, J=56.3, 4.4 Hz, 1H), 3.70 (br s, 2H),3.44 (br s, 2H), 2.48-2.39 (m, 1H), 2.26-2.15 (m, 1H), 2.15-1.98 (m,2H), 1.80-1.65 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.23, −115.09(dtd, J=56.7, 18.6, 6.6 Hz).

Example 454.(R)-5-(8-(3-(2,2-difluoroethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3-(2,2-difluoroethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with (3R)-3-(2,2-difluoroethyl)pyrrolidinehydrochloride. Purification was accomplished by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier, Gemini column). ES/MS m/z: 363.1 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.44-11.28 (m, 2H), 8.04 (d, J=1.2 Hz, 1H), 7.94 (d,J=6.1 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 6.60 (s, 1H), 6.21 (tt, J=56.4,4.4 Hz, 1H), 3.72 (m, 2H), 3.60-3.23 (m, 2H), 2.48-2.41 (m, 1H),2.26-2.15 (m, 1H), 2.15-1.98 (m, 2H), 1.74 (dq, J=12.0, 9.5 Hz, 1H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −75.27, −115.09 (dtd, J=56.5, 18.5, 5.9 Hz).

Example 455.5-(3-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-chloro-8-(3-fluoro-3-(trifluoromethyl)azetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3-fluoro-3-(trifluoromethyl)azetidinehydrochloride. Purification was accomplished by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier, Gemini column). ES/MS m/z: 405.0 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.47 (d, J=2.1 Hz, 1H), 11.43 (dd, J=6.2, 2.1 Hz, 1H),7.99 (d, J=6.1 Hz, 1H), 7.72 (s, 1H), 6.71 (s, 1H), 4.97-4.73 (m, 4H).¹⁹F NMR (376 MHz, DMSO-d6) δ −75.15, −82.88 (d, J=7.6 Hz),−172.18-−172.69 (m).

Example 456.5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows:5-bromo-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidine(120 mg, 0.275 mmol), (2,4-ditert-butoxypyrimidin-5-yl)boronic acid(88.5 mg, 0.330 mmol), cesium carbonate (269 mg, 0.825 mmol), andPd(dppf)Cl₂—CH₂Cl₂ (22.5 mg, 0.0275 mmol) were weighed into a microwavevial, and dioxane (2 mL) and water (0.5 mL) were added. The mixture wasdegassed with N2, and the vial was sealed and heated to 80° C. for 16 h.The mixture was then cooled to room temperature, and TFA (1 mL) wasadded slowly. The mixture was stirred at room temperature for anadditional 20 min, then concentrated and purified by RP-HPLC (10-90%MeCN/H₂O with TFA modifier, Gemini column). ES/MS m/z: 468.1 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.62 (dd, J=6.4, 2.0 Hz, 1H), 11.52 (d, J=1.9Hz, 1H), 8.35 (d, J=6.3 Hz, 1H), 8.19-8.07 (m, 2H), 7.80-7.65 (m, 3H),7.18 (dd, J=8.4, 1.4 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 5.41 (q, J=9.1 Hz,2H), 3.15 (ddd, J=8.3, 6.6, 4.5 Hz, 1H), 2.84-2.74 (m, 1H), 1.95 (ddd,J=8.3, 6.6, 1.5 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.08 (t, J=9.0Hz), —75.62.

Example 457.5-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamide

5-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamidewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-((6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-isopropylpentanamide.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 423.2 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.66-11.48 (m, 2H), 8.33 (d, J=1.3 Hz, 1H), 8.06 (d, J=6.1Hz, 1H), 7.88-7.80 (m, 2H), 7.46 (s, 1H), 4.75 (t, J=12.7 Hz, 2H),3.86-3.77 (m, 1H), 2.43-2.27 (m, 4H), 1.03 (d, J=6.5 Hz, 6H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −75.17, −105.77 (tt, J=17.7, 12.2 Hz).

Example 458.5-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamide

5-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamidewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith5-((6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-4,4-difluoro-N-(2,2,2-trifluoroethyl)pentanamide.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 463.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.56 (d, J=6.1 Hz, 2H), 8.69 (t, J=6.4 Hz, 1H), 8.31 (d,J=1.4 Hz, 1H), 8.05 (d, J=6.1 Hz, 1H), 7.80 (d, J=1.4 Hz, 1H), 7.43 (s,1H), 4.76 (t, J=12.7 Hz, 2H), 3.91 (qd, J=9.9, 6.3 Hz, 2H), 2.49-2.31(m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −71.26-−71.51 (m), −75.07, −106.02(ddd, J=26.1, 17.2, 12.4 Hz).

Example 459.5-(8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(3-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 502.2 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.55 (d, J=3.8 Hz, 2H), 8.33 (d, J=1.4 Hz, 1H), 8.04 (d,J=6.4 Hz, 1H), 7.86 (s, 1H), 7.81 (s, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.60(s, 1H), 7.25 (dd, J=8.5, 1.2 Hz, 1H), 5.44 (q, J=9.0 Hz, 2H), 3.04(ddd, J=9.3, 6.1, 4.3 Hz, 1H), 2.87-2.79 (m, 1H), 2.17 (dt, J=9.0, 5.3Hz, 1H), 1.93 (dt, J=8.5, 5.2 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−70.17 (t, J=9.0 Hz), −75.13.

Example 460.5-(8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 502.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.52 (d, J=5.3 Hz, 2H), 8.30 (s, 1H), 8.23 (s, 1H), 8.02 (d,J=6.1 Hz, 1H), 7.80 (s, 1H), 7.77 (s, 1H), 7.56 (s, 1H), 7.25 (s, 1H),5.45 (q, J=9.1 Hz, 2H), 3.04 (dt, J=9.4, 5.4 Hz, 1H), 2.82 (dt, J=10.0,5.5 Hz, 1H), 2.17 (dt, J=10.6, 5.2 Hz, 1H), 1.96-1.88 (m, 1H). ¹⁹F NMR(376 MHz, DMSO-d6) δ −70.09 (t, J=9.1 Hz), −74.90.

Example 461.5-(8-((1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(1H-benzo[d]imidazol-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture) and purified by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 386.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.81 (dd, J=6.2, 2.0 Hz, 1H), 11.62 (d, J=2.0 Hz, 1H), 8.55 (d, J=1.7Hz, 1H), 8.20-8.07 (m, 2H), 7.97 (s, 1H), 7.76 (dt, J=6.7, 3.3 Hz, 2H),7.53 (dd, J=6.1, 3.1 Hz, 2H), 3.50 (td, J=7.4, 4.4 Hz, 1H), 3.32-3.22(m, 1H), 2.48 (d, J=10.8 Hz, 2H).

Example 462.(1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-N-phenylcyclopropane-1-carboxamide

(1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-N-phenylcyclopropane-1-carboxamidewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-N-phenylcyclopropane-1-carboxamide(racemic mixture) and purified by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 389.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.65-11.53 (m, 2H), 10.43 (s, 1H), 8.38 (d, J=1.4 Hz, 1H), 8.05 (d,J=6.1 Hz, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.65 (s, 1H), 7.64-7.56 (m, 2H),7.34-7.26 (m, 2H), 7.04 (td, J=7.3, 1.2 Hz, 1H), 2.86 (ddd, J=9.5, 6.1,4.0 Hz, 1H), 2.82-2.74 (m, 1H), 1.90 (ddd, J=8.5, 6.2, 3.9 Hz, 1H), 1.68(ddd, J=9.3, 5.6, 3.8 Hz, 1H).

Example 463.5-(8-((1S,2S)-2-(2-hydroxypropan-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-hydroxypropan-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)propan-2-ol(racemic mixture) and purified by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini column). ES/MS m/z: 328.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.63-11.47 (m, 2H), 8.36 (s, 1H), 8.02 (d, J=6.1 Hz, 1H), 7.95 (s, 1H),7.48 (s, 1H), 2.47 (d, J=5.4 Hz, 1H), 1.78-1.67 (m, 1H), 1.41-1.31 (m,1H), 1.27 (dd, J=9.2, 4.7 Hz, 1H), 1.21 (s, 3H), 1.19 (s, 3H).

Example 464.5-(8-((1S,2S)-2-(2,3,4-trifluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2,3,4-trifluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described forIntermediate 81, but replacing 8-bromo-6-chloro-imidazo[1,2-b]pyridazinewith 5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand racemic2-[(1S,2S)-2-(3,5-difluorophenyl)cyclopropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewith4,4,5,5-tetramethyl-2-((1S,2S)-2-(2,3,4-trifluorophenyl)cyclopropyl)-1,3,2-dioxaborolane,and purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 400.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.50 (d, J=6.3 Hz, 2H),8.27 (s, 1H), 8.00 (d, J=6.0 Hz, 1H), 7.76 (s, 1H), 7.55 (s, 1H),7.37-7.25 (m, 1H), 7.22-7.12 (m, 1H), 3.02 (dt, J=10.3, 5.6 Hz, 1H),2.74 (q, J=4.4 Hz, 1H), 2.13 (dt, J=9.9, 5.2 Hz, 1H), 1.79 (dt, J=8.8,5.2 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −74.56 (s, 3F), −138.66 (m,1F), −141.38 (m, 1F), −162.67 (m, 1F).

Example 465.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrileand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 371.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=6.3 Hz, 2H),8.34 (s, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J=8.2 Hz,2H), 7.59 (s, 1H), 7.46 (d, J=8.3 Hz, 2H), 2.95-2.86 (m, 1H), 2.83 (dt,J=9.8, 5.4 Hz, 1H), 2.16 (dt, J=8.7, 5.5 Hz, 1H), 1.86 (dt, J=8.8, 5.5Hz, 1H).

Example 466.3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrile

3-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrilewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-fluorobenzonitrileand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 389.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=5.5 Hz, 2H),8.36 (d, J=1.4 Hz, 1H), 8.03 (d, J=6.1 Hz, 1H), 7.90 (s, 1H), 7.86 (dd,J=7.1, 2.1 Hz, 1H), 7.81 (ddd, J=8.5, 4.8, 2.1 Hz, 1H), 7.66 (s, 1H),7.43 (dd, J=10.0, 8.5 Hz, 1H), 3.02 (ddd, J=9.0, 6.2, 4.5 Hz, 1H),2.88-2.79 (m, 1H), 2.13 (dt, J=8.9, 5.3 Hz, 1H), 2.02-1.85 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −75.18 (s, 3F), −110.52 (p, J=5.4 Hz, 1F).

Example 467.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluorobenzonitrileand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 389.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (d, J=4.2 Hz, 2H),8.32 (d, J=1.4 Hz, 1H), 8.02 (d, J=6.3 Hz, 1H), 7.90-7.81 (m, 2H), 7.59(s, 1H), 7.47 (dd, J=11.0, 1.6 Hz, 1H), 7.34 (dd, J=8.1, 1.6 Hz, 1H),2.96 (m, 1H), 2.85 (m, 1H), 2.23 (dt, J=8.8, 5.5 Hz, 1H), 1.89 (dt,J=8.8, 5.3 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.15 (s, 3F), −109.51(dd, J=11.1, 7.1 Hz, 1F).

Example 468.5-(8-((1S,2S)-2-(2,3,6-trifluorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a reaction vessel containing5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (124mg, 0.40 mmol, 1.2 equiv.), racemic4,4,5,5-tetramethyl-2-((1S,2S)-2-(2,3,6-trifluorophenyl)cyclopropyl)-1,3,2-dioxaborolane(100 mg, 0.34 mmol, 1 equiv.), CataCXium A Pd G3 (12 mg, 0.017 mmol, 5mol %) and K₃PO₄ (214 mg, 1.0 mmol, 3 equiv.) was added a mixture offreshly degassed dioxane/water (1.98 mL, 5:1 ratio) under an atmosphereof nitrogen. The reaction was heated to 120° C. and stirred overnight.The reaction mixture was subsequently cooled to room temperature,diluted with DMF/water, filtered and purified by RP-HPLC (10-90%MeCN/H₂O with TFA, Gemini column). 400.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.54 (m, 2H), 8.33 (d, J=1.4 Hz, 1H), 8.02 (d, J=6.3 Hz,1H), 7.85 (s, 1H), 7.63 (s, 1H), 7.41 (qd, J=9.5, 5.0 Hz, 1H), 7.13(tdd, J=9.5, 4.1, 2.1 Hz, 1H), 2.99-2.89 (m, 2H), 2.12 (dt, J=9.7, 5.3Hz, 1H), 1.89 (ddd, J=8.6, 6.8, 4.7 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6)δ −75.03 (s, 3F), −119.95 (ddt, J=14.7, 9.3, 4.3 Hz, 1F),−139.15-−139.84 (m, 1F), −143.41 (dddd, J=21.7, 14.5, 10.1, 4.1 Hz, 1F).

Example 469.5-(7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((1S,2S)-2-(2,4-difluorophenyl)cyclopropyl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine.The reaction was stirred at 80° C. for only 1 hour before workup andpurification by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 382.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.64-11.54 (m, 1H), 11.50(d, J=2.0 Hz, 1H), 8.33 (d, J=6.4 Hz, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.69(s, 1H), 7.46 (td, J=8.8, 6.5 Hz, 1H), 7.24 (ddd, J=10.7, 9.3, 2.6 Hz,1H), 7.15-7.03 (m, 1H), 6.65 (d, J=2.3 Hz, 1H), 3.06 (ddd, J=8.8, 6.1,4.7 Hz, 1H), 2.71-2.61 (m, 1H), 1.93-1.77 (m, 2H). ¹⁹F NMR (376 MHz,DMSO-d6) δ −75.08 (s, 3F), −113.08 (ddd, J=15.2, 8.8, 6.4 Hz, 1F),−115.44 (td, J=9.8, 7.0 Hz, 1F).

Example 470.5-(3-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a solution of5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(25 mg, 0.043 mmol, 1 equiv.) in DMF (0.5 mL) was added Palau' Chlor (9mg, 0.043 mmol, 1 equiv) at room temperature. The reaction was stirredfor 4 hours before being diluted with DMF/water and purified by RP-HPLC(10-90% MeCN/H₂O with TFA, Gemini column). ES/MS m/z: 502.10 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.63-11.49 (m, 2H), 8.15 (s, 1H), 8.04 (d,J=6.0 Hz, 1H), 7.84 (s, 1H), 7.77-7.67 (m, 2H), 7.59 (s, 1H), 7.12 (dd,J=8.5, 1.1 Hz, 1H), 5.40 (q, J=9.1 Hz, 2H), 3.01 (ddd, J=9.0, 6.2, 4.3Hz, 1H), 2.81 (ddd, J=8.9, 5.9, 4.4 Hz, 1H), 2.16 (dt, J=8.8, 5.2 Hz,1H), 1.95-1.84 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.08 (t, J=9.2Hz, 3F), −75.40 (s, 3F).

Example 471.5-(3-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-chloro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as racemic mixture in the manner described for Example 470,but replacing5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewith racemic5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 503.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58-11.51 (m, 2H), 9.14(s, 1H), 8.46 (s, 1H), 8.05 (d, J=6.1 Hz, 1H), 7.93 (s, 1H), 7.85 (s,1H), 7.63 (s, 1H), 5.46 (q, J=9.1 Hz, 2H), 3.19 (q, J=7.4, 6.2 Hz, 1H),3.06 (ddd, J=9.8, 6.0, 4.1 Hz, 1H), 2.16 (dt, J=9.4, 5.0 Hz, 1H), 2.01(dt, J=9.6, 4.5 Hz, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.14 (t, J=9.2Hz, 3F), −74.82 (s, 3F).

Example 472.5-(7-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((3R,4S)-3,4-difluoropyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyrimidineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 336.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.71-11.57 (m, 1H), 11.51(d, J=2.0 Hz, 1H), 8.47 (d, J=6.4 Hz, 1H), 8.42 (s, 1H), 7.42 (s, 1H),5.56 (dt, J=11.4, 4.9 Hz, 1H), 5.49-5.35 (m, 1H), 4.35 (d, J=17.4 Hz,2H), 4.13 (t, J=16.5 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.17 (s,3F), −205.98 (m, 2F).

Example 473.5-(8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 442, but replacing6-azabicyclo[3.2.0]heptane with 3,3-difluoro-4-methoxypyrrolidinehydrochloride and purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Geminicolumn). ES/MS m/z: 365.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41 (d,J=2.0 Hz, 1H), 11.39-11.34 (m, 1H), 8.07 (d, J=1.2 Hz, 1H), 7.93 (d,J=6.1 Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 6.59 (s, 1H), 4.45 (d, J=11.6 Hz,1H), 4.35-4.20 (m, 2H), 4.05-3.85 (m, 2H), 3.48 (s, 3H). ¹⁹F NMR (376MHz, DMSO-d6) δ −75.14 (s, 3F), −107.10 (d, J=234.7 Hz, 1F), −121.69 (d,J=235.0 Hz, 1F).

Example 474.5-(8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3,3-difluoro-4-methoxypyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazineand purified by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini column). ES/MSm/z: 383.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43 (d, J=2.0 Hz, 1H),11.42-11.36 (m, 1H), 7.96 (d, J=6.1 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H),6.59 (s, 1H), 4.42 (s, 1H), 4.35-4.22 (m, 2H), 4.15 (s, 1H), 3.95 (s,1H), 3.48 (s, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −107.22 (d, J=237.3 Hz,1F), −121.87 (d, J=236.2 Hz, 1F), −155.44 (d, J=7.3 Hz, 1F).

Example 475.5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-2-isobutylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-2-isobutylimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(7,7-difluoro-5-azaspiro[2.4]heptan-5-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-2-isobutylimidazo[1,2-b]pyridazineand isolated by filtration as a hydrochloride salt. ES/MS m/z: 417.2[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.42 (d, J=3.8 Hz, 2H), 7.95 (d,J=6.3 Hz, 1H), 7.92 (s, 1H), 6.67 (s, 1H), 4.57 (t, J=12.4 Hz, 2H), 3.95(s, 2H), 2.58 (d, J=7.0 Hz, 2H), 2.03 (dq, J=13.5, 6.7 Hz, 1H),1.08-1.02 (m, 2H), 1.00 (t, J=3.1 Hz, 2H), 0.93 (d, J=6.6 Hz, 6H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −107.32 (t, J=12.5 Hz, 2F).

Example 476.5-(8-(cis-3-azabicyclo[3.2.0]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (45 mg,0.15 mmol), 3-azabicyclo[3.2.0]heptane hydrochloride (33 mg, 0.25 mmol),and DIPEA (0.10 mL, mmol) were combined in NMP (0.3 mL) and stirred at120° C. for 3 hours. The mixture was cooled, diluted with water, TFA,and MeCN, and purified by RP-HPLC (5-40% MeCN/H₂O with TFA modifier)affording5-(8-(cis-3-azabicyclo[3.2.0]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ES/MS m/z: 325.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.40(d, J=2.0 Hz, 1H), 11.37 (d, J=6.4 Hz, 1H), 8.05 (d, J=1.2 Hz, 1H), 7.95(d, J=6.1 Hz, 1H), 7.58 (s, 1H), 6.73 (s, 1H), 4.29 (s, 2H), 3.08 (d,J=7.1 Hz, 2H), 2.24 (dt, J=9.6, 5.7 Hz, 2H), 1.74 (qd, J=6.6, 3.9 Hz,2H).

Example 477.(S)-5-(8-(2-(methoxymethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(2-(methoxymethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with (S)-2-(methoxymethyl)pyrrolidine. ES/MSm/z: 343.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.39 (d, J=2.0 Hz, 1H),11.36 (dd, J=6.2, 2.0 Hz, 1H), 8.03 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 6.69 (s, 1H), 5.04 (s, 1H), 3.79 (s,1H), 3.57 (dd, J=9.5, 3.7 Hz, 1H), 3.39 (dd, J=9.4, 7.5 Hz, 1H),3.33-3.22 (m, 4H), 2.15-1.70 (m, 4H).

Example 478.5-(8-(1-fluoro-3-azabicyclo[3.2.0]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(1-fluoro-3-azabicyclo[3.2.0]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 1-fluoro-3-azabicyclo[3.2.0]heptane.ES/MS m/z: 343.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45-11.30 (m, 2H),8.10 (d, J=1.3 Hz, 1H), 7.96 (d, J=6.1 Hz, 1H), 7.63 (d, J=1.3 Hz, 1H),6.70 (s, 1H), 4.50 (t, J=15.5 Hz, 1H), 3.88 (dd, J=11.5, 6.4 Hz, 1H),3.24 (ddt, J=23.4, 15.5, 7.3 Hz, 1H), 2.48-2.31 (m, 2H), 2.22-2.06 (m,1H), 1.34 (p, J=9.7 Hz, 1H).

Example 479.5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 3,3-difluoro-4-methylpyrrolidine. ES/MSm/z: 349.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41 (d, J=1.9 Hz, 1H),11.40-11.30 (m, 1H), 8.06 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H),7.58 (d, J=1.2 Hz, 1H), 6.60 (s, 1H), 4.53-4.17 (m, 4H), 2.85 (dq,J=17.7, 8.9, 8.1 Hz, 1H), 1.15 (d, J=6.9 Hz, 3H).

Example 480.5-(8-(3-oxopyrazolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-oxopyrazolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with pyrazolidin-3-one. ES/MS m/z: 314.1[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 2H), 10.83 (s, 1H), 8.13(s, 1H), 7.98 (d, J=6.1 Hz, 1H), 7.64 (s, 1H), 7.07 (s, 1H), 4.58 (s,2H), 2.77-2.65 (m, 2H).

Example 481.5-(8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-difluoroazetidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 3,3-difluoroazetidine. ES/MS m/z: 321.2[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43 (d, J=2.0 Hz, 1H), 11.40 (d,J=6.6 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.95 (d, J=6.1 Hz, 1H), 7.59 (d,J=1.2 Hz, 1H), 6.60 (s, 1H), 4.79 (t, J=12.3 Hz, 4H).

Example 482.5-(8-(4-(4-fluorobenzyl)-3-oxopiperazin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4-(4-fluorobenzyl)-3-oxopiperazin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 1-(4-fluorobenzyl)piperazin-2-one. ES/MSm/z: 436.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.44 (d, J=2.0 Hz, 1H),11.40 (dd, J=6.2, 2.0 Hz, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.96 (d, J=6.1Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.35 (dd, J=8.6, 5.6 Hz, 2H), 7.23-7.13(m, 2H), 6.90 (s, 1H), 4.59 (d, J=2.8 Hz, 4H), 4.37 (t, J=5.4 Hz, 2H),3.50-3.40 (m, 2H).

Example 483.5-(8-(azepan-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(azepan-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with azepane. ES/MS m/z: 327.2 [M+H]. ¹H NMR(400 MHz, DMSO-d6) δ 11.37 (d, J=2.0 Hz, 1H), 11.34 (d, J=6.6 Hz, 1H),7.99 (d, J=1.1 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.53 (d, J=1.2 Hz, 1H),6.77 (s, 1H), 4.07 (s, 4H), 1.89-1.72 (m, 4H), 1.52 (p, J=2.7 Hz, 4H).

Example 484.5-(8-(4,4-difluoro-5-methylazepan-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(4,4-difluoro-5-methylazepan-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 4,4-difluoro-5-methylazepane. ES/MS m/z:377.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J=1.2 Hz, 1H), 7.94(s, 1H), 7.55 (d, J=1.2 Hz, 1H), 6.72 (s, 1H), 4.37-4.21 (m, 1H),4.19-3.92 (m, 2H), 3.91-3.71 (m, 1H), 2.45-2.17 (m, 3H), 2.03-1.82 (m,2H), 0.99 (d, J=6.9 Hz, 3H).

Example 485.5-(8-((3-hydroxy-3-methylbutyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3-hydroxy-3-methylbutyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 4-amino-2-methylbutan-2-ol. ES/MS m/z:331.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.41 (d, J=8.1Hz, 1H), 8.09 (s, 1H), 7.98 (d, J=6.1 Hz, 1H), 7.66 (s, 1H), 7.43 (t,J=4.2 Hz, 1H), 6.86 (s, 1H), 3.41-3.32 (m, 2H), 1.77 (dd, J=8.7, 6.4 Hz,2H), 1.18 (s, 6H).

Example 486.5-(8-((3-phenylpropyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3-phenylpropyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 3-phenylpropan-1-amine. ES/MS m/z: 363.2[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.50-11.27 (m, 2H), 8.12 (d, J=1.5Hz, 1H), 7.96 (d, J=6.1 Hz, 1H), 7.72 (s, 1H), 7.53 (t, J=5.8 Hz, 1H),7.32-7.22 (m, 4H), 7.22-7.16 (m, 1H), 6.84 (s, 1H), 3.38-3.27 (m, 2H),2.77-2.65 (m, 2H), 1.97 (td, J=8.6, 8.1, 6.2 Hz, 2H).

Example 487.5-(8-(phenethylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(phenethylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-phenylethan-1-amine. ES/MS m/z: 349.1[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 11.39 (d, J=6.7 Hz,1H), 8.05 (d, J=1.4 Hz, 1H), 7.97 (d, J=6.1 Hz, 1H), 7.59 (s, 1H), 7.46(d, J=6.2 Hz, 1H), 7.32 (d, J=4.3 Hz, 4H), 7.23 (q, J=4.3 Hz, 1H), 6.91(s, 1H), 2.98 (q, J=7.4, 7.0 Hz, 2H), 2.49 (m, 2H).

Example 488. tert-butyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate

tert-butyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylatewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with tert-butyl8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate. ES/MS m/z: 475.9[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J=1.2 Hz, 1H), 7.94 (s, 1H),7.57 (d, J=1.2 Hz, 1H), 6.59 (s, 1H), 4.43 (s, 2H), 4.25 (s, 2H),4.12-3.91 (m, 4H), 1.40 (s, 9H).

Example 489.5-(8-((3-(trifluoromethyl)phenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3-(trifluoromethyl)phenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with2-(3-(trifluoromethyl)phenyl)ethan-1-amine. ES/MS m/z: 417.2 [M+H]. ¹HNMR (400 MHz, DMSO-d6+D2O) δ 8.13 (d, J=1.5 Hz, 1H), 7.98 (s, 1H), 7.73(s, 1H), 7.68 (s, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.60-7.49 (m, 2H), 6.96(s, 1H), 3.62 (t, J=7.1 Hz, 2H), 3.08 (t, J=7.2 Hz, 2H). ¹⁹F NMR (376MHz, DMSO-d6+D2O) δ −61.49, −74.74.

Example 490.5-(8-((3-chlorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3-chlorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-(3-chlorophenyl)ethan-1-amine. ES/MSm/z: 383.2 [M+1-1]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.13 (s, 1H), 7.99(s, 1H), 7.72 (s, 1H), 7.41 (t, J=1.8 Hz, 1H), 7.37-7.23 (m, 3H), 6.98(s, 1H), 3.58 (t, J=7.4 Hz, 2H), 2.98 (t, J=7.3 Hz, 2H).

Example 491.5-(8-((2-chlorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2-chlorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-(2-chlorophenyl)ethan-1-amine. ES/MSm/z: 383.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.09 (s, 1H), 7.98 (s,1H), 7.68 (s, 1H), 7.50-7.38 (m, 2H), 7.33-7.23 (m, 2H), 6.97 (s, 1H),3.57 (t, J=7.6 Hz, 2H), 3.14-3.05 (m, 2H).

Example 492.5-(8-((3-fluorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3-fluorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-(3-fluorophenyl)ethan-1-amine. ES/MSm/z: 367.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.10 (s, 1H), 7.99 (s,1H), 7.68 (s, 1H), 7.40-7.30 (m, 1H), 7.23-7.11 (m, 2H), 7.09-7.01 (m,1H), 6.96 (s, 1H), 3.58 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.4 Hz, 2H). ¹⁹FNMR (376 MHz, DMSO-d6+D2O) δ −74.59, −113.99-−114.12 (m)

Example 493.5-(8-((2-fluorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2-fluorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-(2-fluorophenyl)ethan-1-amine. ES/MSm/z: 367.2 [M+1-1]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.10 (s, 1H), 7.98(s, 1H), 7.68 (s, 1H), 7.39 (t, J=7.7 Hz, 1H), 7.29 (q, J=6.2 Hz, 1H),7.21-7.10 (m, 2H), 6.94 (s, 1H), 3.57 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.3Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6+D2O) δ −74.56, −116.41-−121.72 (m).

Example 494.(S)-5-(8-((2-fluoro-2-phenylethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(5)-5-(8-((2-fluoro-2-phenylethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with (S)-2-fluoro-2-phenylethan-1-amine.ES/MS m/z: 367.1 [M+1-1]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.11 (s, 1H),7.98 (s, 1H), 7.69 (s, 1H), 7.56-7.36 (m, 5H), 7.00 (s, 1H), 5.96-5.75(m, 1H), 3.97-3.73 (m, 2H).

Example 495.5-(8-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2-(5-chloro-1H-indol-3-yl)ethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-(5-chloro-1H-indol-3-yl)ethan-1-amine.ES/MS m/z: 422.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.04 (s, 1H),7.94 (s, 1H), 7.64-7.62 (m, 1H), 7.58 (d, J=20.3 Hz, 2H), 7.42-7.29 (m,3H), 7.17-7.02 (m, 1H), 6.83 (s, 1H), 3.65-3.54 (m, 2H), 3.06 (t, J=7.3Hz, 2H).

Example 496.5-(8-((4-fluorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((4-fluorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-(4-fluorophenyl)ethan-1-amine. ES/MSm/z: 367.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.07 (s, 1H), 7.98 (s,1H), 7.64 (s, 1H), 7.34 (dd, J=8.6, 5.6 Hz, 2H), 7.12 (t, J=8.8 Hz, 2H),6.91 (s, 1H), 3.53 (t, J=7.8 Hz, 2H), 2.95 (t, J=7.4 Hz, 2H). ¹⁹F NMR(376 MHz, DMSO-d6+D2O) δ −74.45, −117.41.

Example 497.5-(8-((4-chlorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((4-chlorophenethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2-(4-chlorophenyl)ethan-1-amine. ES/MSm/z: 383.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.03 (s, 1H), 7.96 (s,1H), 7.59 (s, 1H), 7.40-7.28 (m, 4H), 6.84 (s, 1H), 3.54 (s, 2H), 2.95(t, J=7.4 Hz, 2H).

Example 498.5-(8-((2,2-difluoro-2-phenylethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2,2-difluoro-2-phenylethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with 2,2-difluoro-2-phenylethan-1-amine.ES/MS m/z: 385.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.13 (d, J=1.4Hz, 1H), 7.96 (s, 1H), 7.71 (s, 1H), 7.64-7.57 (m, 2H), 7.56-7.48 (m,3H), 7.09 (s, 1H), 4.35-4.11 (m, 2H). ¹⁹F NMR (376 MHz, DMSO-d6+D2O) δ−74.81, −99.32.

Example 499.(S)-5-(8-((2-phenylpropyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-((2-phenylpropyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with (S)-2-phenylpropan-1-amine. ES/MS m/z:363.2 [M+H]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.11 (s, 1H), 7.99 (s, 1H),7.70 (s, 1H), 7.37-7.28 (m, 4H), 7.26-7.18 (m, 1H), 6.99 (s, 1H),3.57-3.44 (m, 2H), 3.22 (q, J=7.2 Hz, 1H), 1.29 (d, J=6.9 Hz, 3H).

Example 500.(R)-5-(8-((2-phenylpropyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-((2-phenylpropyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, but replacing3-azabicyclo[3.2.0]heptane with (R)-2-phenylpropan-1-amine. ES/MS m/z:363.2 [M+1-1]. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.11 (s, 1H), 7.99 (s,1H), 7.70 (s, 1H), 7.37-7.28 (m, 4H), 7.26-7.18 (m, 1H), 6.99 (s, 1H),3.57-3.44 (m, 2H), 3.22 (q, J=7.2 Hz, 1H), 1.29 (d, J=6.9 Hz, 3H).

Example 501.5-(8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a suspension of tert-butyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate(148 mg, 0.31 mmol) in MeOH (2 mL) was added 4 M aq HCl (0.8 mL) and thereaction was stirred at 45° C. After 3 hours, the methanol was removedin vacuo and the remaining reaction was lyophilized. The resultingsolids were rinsed with MeOH and dried in vacuo to afford5-(8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a bis HCl salt. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.08 (d, J=1.2 Hz,1H), 7.97 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.64 (s, 1H), 4.54-4.33 (m,4H), 4.20 (app q, J=11.8 Hz, 4H). ¹⁹F NMR (376 MHz, DMSO-d6+D2O) δ−115.45. ES/MS m/z: 376.2 [M+H].

Example 502.5-(8-(8,8-difluoro-2-(3-fluorobenzyl)-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a suspension of5-(8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionebis HCl (15 mg, 0.034 mmol), 3-fluorobenzaldehyde (12.5 mg, 0.10 mmol),and DIPEA (13 mg, 0.10 mmol) in DMF (0.5 mL) was added sodiumtriacetoxyborohydride (35.5 mg, 0.17 mmol). The reaction was warmed to60° C. and stirred for 30 minutes. The mixture was cooled, diluted withwater and TFA, and purified by RP-HPLC (MeCN/H₂O gradient with TFAmodifier) affording5-(8-(8,8-difluoro-2-(3-fluorobenzyl)-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ¹H NMR (400 MHz, DMSO-d6) δ 8.08 (d, J=1.2 Hz, 1H), 7.97(s, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.53 (td, J=8.0, 6.1 Hz, 1H), 7.45-7.35(m, 2H), 7.32 (td, J=8.6, 2.7 Hz, 1H), 6.64 (s, 1H), 4.64-4.15 (m, 10H).ES/MS m/z: 484.1 [M+H].

Example 503.5-(8-(2-acetyl-8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a solution of5-(8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionebis HCl (15 mg, 0.034 mmol) and pyridine (21 mg, 0.27 mmol) in DCM (0.5mL) was added acetic anhydride (20 mg, 0.10 mmol). The reaction wasstirred at room temperature overnight. Additional acetic anhydride (20mg, 0.10 mmol) was added and the reaction was stirred an additional 4hours. The reaction was concentrated to dryness, treated with aq 1M LiOH(0.5 mL) and DMF (0.5 mL), stirred for 10 min, then diluted with TFA andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording5-(8-(2-acetyl-8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.07 (d, J=1.2 Hz, 1H),7.95 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.62 (s, 1H), 4.43 (t, J=13.1 Hz,2H), 4.35 (d, J=9.3 Hz, 1H), 4.32-4.23 (m, 3H), 4.04 (d, J=10.3 Hz, 1H),3.95 (d, J=10.3 Hz, 1H), 1.81 (s, 3H). ES/MS m/z: 418.2 [M+H].

Example 504. Methyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate

Methyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylatewas prepared in the manner described for Example 503, but replacingacetic anhydride with methyl chloroformate. ¹H NMR (400 MHz,DMSO-d6+D2O) δ 8.06 (d, J=1.2 Hz, 1H), 7.94 (s, 1H), 7.57 (d, J=1.2 Hz,1H), 6.60 (s, 1H), 4.53-4.32 (m, 2H), 4.26 (s, 2H), 4.13-4.00 (m, 4H),3.59 (s, 3H). ES/MS m/z: 434.2 [M+H].

Example 505. benzyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate

To a solution of5-(8-(8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionebis HCl (7 mg, 0.016 mmol) and DIPEA (6 mg, mmol) in DMF (0.3 mL) wasadded N-(Benzyloxycarbonyloxy)succinimide (4.9 mg, mmol). After 30 min,the reaction was dilute with aq TFA, and purified by RP-HPLC (MeCN/H₂Ogradient with TFA modifier) affording benzyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylateas a TFA salt. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.08 (d, J=1.1 Hz, 1H),7.95 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 7.41-7.30 (m, 5H), 6.62 (s, 1H),5.08 (s, 2H), 4.53-4.36 (m, 2H), 4.28 (s, 2H), 4.14 (s, 4H). ¹⁹F NMR(376 MHz, DMSO-d6+D2O) δ −75.16, −116.95. ES/MS m/z: 510.1 [M+H].

Example 506. 2,2,2-trifluoroethyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylate

2,2,2-trifluoroethyl6-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2,6-diazaspiro[3.4]octane-2-carboxylatewas prepared in the manner described for Example 505, but replacingN-(Benzyloxycarbonyloxy)succinimide withN-(2,2,2-trifluoroethoxycarbonyloxy)succinimide. ¹H NMR (400 MHz,DMSO-d6+D2O) δ 8.07 (d, J=1.2 Hz, 1H), 7.95 (s, 1H), 7.58 (d, J=1.2 Hz,1H), 6.61 (s, 1H), 4.84-4.62 (m, 2H), 4.45 (s, 2H), 4.29 (s, 2H),4.26-4.11 (m, 4H). ES/MS m/z: 502.2 [M+H].

Example 507.5-(8-(2-(2,2-difluoroethyl)-8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

To a solution of tert-butyl8,8-difluoro-2,6-diazaspiro[3.4]octane-6-carboxylate (75 mg, 0.30 mmol)and DIPEA (87 mg, 0.67 mmol) in MeCN (0.5 mL) was added2,2-difluoroethyl trifluoromethanesulfonate (97 mg, 0.45 mmol). Thereaction was stirred at 40° C. for 20 min, then concentrated to dryness.The residue was treated with aq NH₄Cl (1 mL) and extracted into diethylether (1 mL). The organic fraction was dried over sodium sulfate,filter, and concentrated in vacuo. The resulting crude material wasdissolved in DCM (1 mL) and treated with TFA (0.5 mL). After 10 min, thereaction was again concentrated to dryness.5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (116 mg,0.34 mmol), DIPEA (0.16 g, 1.2 mmol), and NMP (0.6 mL) were added andthe reaction was stirred at 130° C. for 2 hours. The reaction was cooledto rt and excess DIPEA was removed in vacuo. The reaction was dilutedwith water and TFA, and purified by RP-HPLC (MeCN/H₂O gradient with TFAmodifier) affording5-(8-(2-(2,2-difluoroethyl)-8,8-difluoro-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.09 (d, J=1.2 Hz, 1H),7.97 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.65 (s, 1H), 6.30 (tt, J=54.0,3.5 Hz, 1H), 4.43 (s, 4H), 4.36 (d, J=11.1 Hz, 2H), 4.26 (d, J=10.9 Hz,2H), 3.73 (t, J=15.1 Hz, 2H). ES/MS m/z: 440.2 [M+H].

Example 508.5-(8-(8,8-difluoro-2-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(8,8-difluoro-2-(2,2,2-trifluoroethyl)-2,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 507, but replacing2,2-difluoroethyl trifluoromethanesulfonate with 2,2,2-trifluoroethyltrifluoromethanesulfonate. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.08 (d,J=1.2 Hz, 1H), 7.95 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.62 (s, 1H), 4.35(t, J=13.7 Hz, 2H), 4.27 (s, 2H), 3.68 (d, J=8.1 Hz, 2H), 3.53 (d, J=8.2Hz, 2H), 3.35 (q, J=10.2 Hz, 2H). ES/MS m/z: 458.2 [M+H].

Example 509.5-(8-(1-(difluoromethyl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (45 mg,0.15 mmol),1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(71 mg, 0.29 mmol), potassium carbonate (40 mg, 0.29 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5.4 mg,0.0073 mmol) were combined in DMF:water (3:1, 0.5 mL), degassed withargon, and stirred at 120° C. for 20 minutes. The mixture was cooled,diluted with water (0.5 mL) and MeCN (0.5 mL) and the precipitatedproduct was collected by filtration. ¹H NMR (400 MHz, DMSO-d6) δ 9.96(d, J=66.7 Hz, 1H), 9.31 (s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.32 (s,1H), 8.20 (d, J=1.2 Hz, 1H), 7.99 (t, J=58.8 Hz, 1H), 7.70 (d, J=1.2 Hz,1H). ES/MS m/z: 346.1 [M+H].

Example 510.5-(8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 509, but replacing1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith (1-(2-methoxyethyl)-1H-pyrazol-4-yl)boronic acid. The desiredproduct was purified by RP-HPLC (MeCN/H₂O gradient with TFA modifier).¹H NMR (400 MHz, DMSO-d6) δ 11.53 (d, J=1.8 Hz, 1H), 11.49 (d, J=6.6 Hz,1H), 8.87 (s, 1H), 8.43 (s, 1H), 8.28 (d, J=1.2 Hz, 1H), 8.02 (d, J=6.1Hz, 1H), 7.91 (s, 1H), 7.80 (d, J=1.2 Hz, 1H), 4.41 (t, J=5.2 Hz, 2H),3.75 (t, J=5.2 Hz, 2H), 3.26 (s, 3H). ES/MS m/z: 354.2 [M+H].

Example 511.5-(8-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 509, but replacing1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolewith4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)morpholine.The desired product was purified by RP-HPLC (MeCN/H₂O gradient with TFAmodifier). ¹H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 2H), 11.52 (s, 1H),9.06 (s, 1H), 8.53 (s, 1H), 8.30 (d, J=1.2 Hz, 1H), 8.03 (d, J=6.0 Hz,1H), 7.96 (s, 1H), 7.81 (d, J=1.2 Hz, 1H), 4.72 (t, J=6.4 Hz, 2H),4.17-3.90 (m, 4H), 3.19 (s, 4H). ES/MS m/z: 409.2 [M+H].

Example 512.5-(8-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (20 mg,0.065 mmol), 1-methyl-3-(tributylstannyl)-1H-pyrazole (48 mg, 0.13mmol), cesium carbonate (42 mg, 0.13 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (2.4 mg,0.0033 mmol) were combined in DMF (0.3 mL), degassed with argon, andstirred at 110° C. for 3 hours. The mixture was cooled, rinsed withhexanes (2×1 mL), diluted with water and TFA and purified by RP-HPLC(MeCN/H₂O gradient with TFA modifier) affording5-(8-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J=4.7 Hz, 2H), 8.41(s, 1H), 8.36 (s, 1H), 8.09 (d, J=6.3 Hz, 1H), 7.94 (d, J=2.3 Hz, 2H),7.52 (d, J=2.3 Hz, 1H), 4.03 (s, 3H). ES/MS m/z: 310.1 [M+H].

Example 513.5-(8-(4,4-dimethyl-2-oxopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (25 mg,0.081 mmol), 4,4-dimethylpyrrolidin-2-one (18 mg, 0.16 mmol), cesiumcarbonate (79 mg, 0.24 mmol), and Xantphos Pd G3 (3.9 mg, 0.0041 mmol)were combined in DMF (0.5 mL), degassed with argon, and stirred at 110°C. for 2 hours. The mixture was cooled, diluted with water and TFA andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording5-(8-(4,4-dimethyl-2-oxopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ¹H NMR (400 MHz, DMSO-d6) δ 11.56-11.52 (m, 1H), 11.51(s, 1H), 8.36 (s, 1H), 8.33 (d, J=1.3 Hz, 1H), 8.03 (d, J=6.1 Hz, 1H),7.82 (d, J=1.3 Hz, 1H), 4.25 (s, 2H), 2.46 (s, 2H), 1.21 (s, 6H). ES/MSm/z: 341.2 [M+H].

Example 514.5-(8-(5,5-dimethyl-2-oxooxazolidin-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(5,5-dimethyl-2-oxooxazolidin-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 513, but replacing4,4-dimethylpyrrolidin-2-one with 5,5-dimethyloxazolidin-2-one. ¹H NMR(400 MHz, DMSO-d6) δ 11.49 (d, J=4.8 Hz, 2H), 8.37 (s, 1H), 8.29 (d,J=1.2 Hz, 1H), 8.00 (d, J=6.3 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 4.64 (s,2H), 1.53 (s, 6H). ES/MS m/z: 343.1 [M+H].

Example 515.5-(2,3-dichloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione (72 mg,0.23 mmol) and N-chlorosuccinimide (53 mg, 0.40 mmol) were combined inDMF (1 mL) and stirred overnight at 50° C. The mixture was quenched withaq Na₂S₂O₃ (0.3 mL), stirred for 15 min, then diluted with additionalwater (1 mL). was added and the mixture was stirred at room temperaturefor 30 minutes.5-(8-bromo-2,3-dichloro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas collected by filtration and dried in vacuo. ¹H NMR (400 MHz,DMSO-d6+D2O) δ 8.30 (s, 1H), 8.12 (s, 1H). ES/MS m/z: 377.9 [M+H].

The resulting solids were combined with3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride (37 mg, 0.22 mmol),DIPEA (0.1 mL, 0.58 mmol), and NMP (0.5 mL) and stirred at 120° C. for25 minutes. The mixture was cooled to room temperature and diluted withwater and TFA. The precipitated solids were collected, dissolved in DMFand purified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording5-(2,3-dichloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.35 (m, 2H), 8.01 (d, J=6.2 Hz, 1H),6.82 (s, 1H), 4.36 (s, 2H), 3.84 (s, 2H), 1.21 (s, 6H). ES/MS m/z: 431.1[M+H].

Examples 516 and 517.(S)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Rac-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 476, then separated bychiral SFC chromatography (AD-H column, 30% EtOH cosolvent) affordingenantiomers(S)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6) δ 11.41 (d, J=1.9 Hz, 1H), 11.40-11.30 (m,1H), 8.06 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.58 (d, J=1.2 Hz,1H), 6.60 (s, 1H), 4.53-4.17 (m, 4H), 2.85 (dq, J=17.7, 8.9, 8.1 Hz,1H), 1.15 (d, J=6.9 Hz, 3H). ES/MS m/z: 349.2 [M+H].

Example 518 and 519.(S)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

8-bromo-6-chloro-3-fluoro-imidazo[1,2-b]pyridazine (220 mg, 0.88 mmol),3,3-difluoro-4-methyl-pyrrolidine hydrochloride (159 mg, 1.0 mmol), andDIPEA (0.46 mL, 2.6 mmol) were combined in MeCN (2 mL) and stirred at80° C. for 35 minutes. The mixture was cooled, diluted with water, andextracted into DCM. The organic layer was rinsed with aq NH₄Cl andbrine, dried over Na₂SO₄, and concentrated in vacuo affording6-chloro-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazine.¹H NMR (400 MHz, Chloroform-d) δ 7.17 (d, J=7.2 Hz, 1H), 5.76 (s, 1H),4.31 (s, 3H), 3.66 (s, 1H), 2.73 (tt, J=16.3, 8.1 Hz, 1H), 1.28-1.20 (m,3H). ¹⁹F NMR (376 MHz, Chloroform-d) δ −110.09 (q, J=9.6 Hz), −110.71(td, J=9.9, 6.9 Hz), −152.96 (d, J=7.2 Hz). ES/MS m/z: 291.2 [M+H].

6-chloro-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazine(291 mg, 0.88 mmol), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (483mg, 1.8 mmol), potassium carbonate (335 mg, 2.42 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (52 mg,0.07 mmol) were combined in dioxane:water (5:1, 5 mL), degassed withargon, and stirred at 105° C. for 3 hours. The reaction was cooled, andadditional (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (483 mg, 1.8mmol), potassium carbonate (335 mg, 2.42 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (52 mg,0.07 mmol) were added. The reaction was degassed with argon, andstirring was continued at 105° C. for 1.5 hours. The reaction wascooled, diluted with EtOAc, rinsed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography (3% EtOAc in hexanes→20% EtOAc in hexanes) to provide6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazine.¹H NMR (400 MHz, Chloroform-d) δ 8.69 (s, 1H), 7.19 (d, J=7.2 Hz, 1H),6.22 (s, 1H), 4.60-4.14 (m, 3H), 3.70-3.56 (m, 1H), 2.74 (tt, J=16.2,8.1 Hz, 1H), 1.69 (s, 9H), 1.68 (s, 9H), 1.27 (d, J=6.8 Hz, 3H). ES/MSm/z: 479.1 [M+H].

The enantiomers of6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazinewere then separated by chiral SFC chromatography (AD-H column, 5%EtOH-NH₃ cosolvent) and treated with TFA (0.2 mL) in DCM/MeCN (1:1, 1mL). After 30 minutes, the reaction was concentrated to provideenantiomers(S)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 11.41 (d, J=6.7 Hz, 1H), 7.97(d, J=6.1 Hz, 1H), 7.41 (d, J=7.2 Hz, 1H), 6.60 (s, 1H), 4.32 (s, 1H),3.80 (s, 2H), 3.52 (s, 1H), 2.86 (dt, J=18.0, 8.9 Hz, 1H), 1.15 (d,J=6.8 Hz, 3H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −109.94 (d, J=225.7 Hz),−113.75 (d, J=222.6 Hz), −155.51 (d, J=7.3 Hz). ES/MS m/z: 367.2 [M+H].

Example 520 and 521.(S)-5-(3-chloro-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(3-chloro-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionehydrochloride (72 mg, 0.21 mmol) and DIPEA (0.23 mL, 1.3 mmol) werecombined in DMF (1 mL). N-chlorosuccinimide (27 mg, 0.20 mmol) was addedand the reaction was stirred overnight room temperature. An additionalaliquot of N-chlorosuccinimide (27 mg, 0.20 mmol) was added, andstirring was continued at 30° C. for 6 hours. The reaction was quenchedwith aq Na2S2O3 (0.3 mL), stirred for 2 min, then diluted withadditional water (1 mL) and stirred at room temperature for 10 minutes.5-(8-bromo-3-chloro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas collected by filtration and dried in vacuo. ¹H NMR (400 MHz,DMSO-d6+D2O) δ 8.22 (s, 1H), 8.11 (s, 1H), 7.97 (s, 1H). ES/MS m/z:344.0 [M+H].

5-(8-bromo-3-chloro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione(49 mg, 0.10 mmol), 3,3-difluoro-4-methyl-pyrrolidine hydrochloride (36mg, 0.23 mmol), and DIPEA (0.09 mL, 0.50 mmol) were combined in NMP (0.5mL) and stirred at 125° C. for 3 hours. The mixture was cooled, dilutedwith water and TFA, the purified by RP-HPLC (MeCN/H₂O gradient with TFAmodifier) affording5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-chloroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.00 (s, 1H), 7.70 (s, 1H), 6.70 (s,1H), 4.61-4.16 (m, 3H), 3.52 (s, 1H), 2.94-2.79 (m, 1H), 1.15 (d, J=6.8Hz, 3H). ES/MS m/z: 383.2 [M+H].

The enantiomers of5-(8-(3,3-difluoro-4-methylpyrrolidin-1-yl)-3-chloroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere then separated by chiral SFC chromatography (AD-H column, 35%EtOH-TFA cosolvent) and purified by RP-HPLC (MeCN/H₂O gradient with TFAmodifier) affording enantiomers(S)-5-(3-chloro-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(3-chloro-8-(3,3-difluoro-4-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.00 (s, 1H), 7.70 (s, 1H), 6.70 (s,1H), 4.61-4.16 (m, 3H), 3.52 (s, 1H), 2.94-2.79 (m, 1H), 1.15 (d, J=6.8Hz, 3H). ES/MS m/z: 383.2 [M+H].

Example 522.5-(3-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionehydrochloride (50 mg, 0.16 mmol) was combined withN-Fluoro-N′-chloromethyltriethylenediamine bis(tetrafluoroborate) (115mg, 0.32 mmol) in DMF and the reaction was stirred at 50° C. for 30minutes. The reaction was quenched with aq Na2S2O3 (0.3 mL), stirred for15 min, then diluted with additional water (1 mL) and stirred at roomtemperature for 10 minutes.5-(8-bromo-3-chloro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dionewas collected by filtration and dried in vacuo. ¹H NMR (400 MHz,DMSO-d6) δ 11.62 (s, 2H), 8.24 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H). ¹HNMR (400 MHz, DMSO-d6+D2O) δ 8.22 (s, 1H), 8.12 (s, 1H), 7.97 (s, 1H).ES/MS m/z: 344.0 [M+H].

5-(8-bromo-3-chloro-imidazo[1,2-b]pyridazin-6-yl)-1H-pyrimidine-2,4-dione(36 mg, 0.11 mmol), 3,3-difluoro-4,4-dimethyl-pyrrolidine hydrochloride(27 mg, 0.16 mmol), and DIPEA (0.04 mL, 0.21 mmol) were combined in NMP(0.5 mL) and stirred at 120° C. for 1 hour. The mixture was cooled,diluted with water and TFA, the purified by RP-HPLC (MeCN/H₂O gradientwith TFA modifier) affording5-(3-chloro-8-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.69 (s, 1H), 6.67 (s, 1H),4.39 (s, 2H), 3.85 (s, 2H), 1.20 (s, 6H). ES/MS m/z: 397.2 [M+H].

Example 523.5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

8-bromo-6-chloro-imidazo[1,2-b]pyridazine (650 mg, 2.8 mmol),4,4-difluoropyrrolidin-3-ol hydrochloride (490 mg, 3.1 mmol), and DIPEA(1.5 mL, 8.4 mmol) were combined in MeCN (5 mL) and stirred at 55° C.for 3 hours. The mixture was cooled, diluted with water, and extractedinto DCM. The organic layer was rinsed with aq NH₄Cl and brine, driedover Na₂SO₄, and concentrated in vacuo. Purification using flash columnchromatography (10% EtOAc→50% EtOAc in hexanes) afforded1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 275.2 [M+H].

1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(708 mg, 2.58 mmol), (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid(2.77 g, 10.3 mmol), potassium carbonate (1.8 g, 12.9 mmol), and[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (287 mg,0.39 mmol) were combined in dioxane:water (5:1, 20 mL), degassed withargon, and stirred at 90° C. for 2 hours. The reaction was cooled, andadditional (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid (1.5 g, 5.6mmol), potassium carbonate (1.5 g, 11 mmol), and SPhos Pd G3 (150 mg,0.19 mmol) were added. The reaction was degassed with argon, andstirring was continued at 90° C. for 1 hour. The reaction was cooled,diluted with EtOAc, rinsed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash columnaffording1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.¹H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 7.87 (d, J=1.2 Hz, 1H),7.59 (d, J=1.2 Hz, 1H), 6.32 (s, 1H), 4.62-4.32 (m, 3H), 4.26-4.06 (m,2H), 2.58 (s, 1H), 1.70 (s, 9H), 1.68 (s, 9H). ¹⁹F NMR (376 MHz,Chloroform-d) δ −109.56 (d, J=242.5 Hz), −123.80-−126.09 (m). ¹⁹F NMR(376 MHz, Chloroform-d) δ −108.49-−111.08 (m), −123.79-−126.52 (m).ES/MS m/z: 463.1 [M+H].

1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(30 mg, 0.065 mmol), cesium carbonate (63 mg, 0.19 mmol), and2-fluoro-5-(trifluoromethyl)pyridine (21 mg, 0.13 mmol) were combined inNMP (0.1 mL) and stirred at 85° C. for 80 minutes. The reaction wascooled to rt, treated with TFA (0.4 mL), then diluted with water andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6) δ 8.68 (dd, J=2.3, 1.2 Hz, 1H), 8.18 (dd,J=8.8, 2.6 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.95 (s, 1H), 7.60 (d, J=1.1Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.64 (s, 1H), 6.26-5.95 (m, 1H),4.91-4.36 (m, 3H), 4.20 (d, J=12.7 Hz, 1H). ¹⁹F NMR (377 MHz, DMSO-d6) δ−60.58, −75.26, −107.94 (d, J=237.8 Hz), −119.52 (d, J=238.5 Hz). ES/MSm/z: 496.1 [M+H].

Example 524.5-(8-(4-(2,2-difluoroethoxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(30 mg, 0.065 mmol) and sodium hydride (60% dispersion in oil, 7.5 mg,mmol) were combined in THF (0.8 mL) at 5° C. After 15 minutes,2,2-difluoroethyl trifluoromethanesulfonate (28 mg, 0.13 mmol) wasadded. The reaction was stirred overnight, while allowing to slowly warmto room temperature. The reaction was treated with water (0.2 mL) andTFA (0.2 mL), concentrated to dryness, then purified by RP-HPLC(MeCN/H₂O gradient with TFA modifier) affording5-(8-(4-(2,2-difluoroethoxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.07 (d, J=1.2 Hz, 1H), 7.94 (s, 1H),7.59 (d, J=1.2 Hz, 1H), 6.60 (s, 1H), 6.19 (tt, J=54.6, 3.5 Hz, 1H),4.66-4.51 (m, 1H), 4.53-4.38 (m, 1H), 4.37-4.24 (m, 1H), 4.24-4.14 (m,1H), 4.01 (app s, 1H), 3.99 (td, J=15.1, 3.6 Hz, 2H). ¹⁹F NMR (376 MHz,DMSO-d6+D2O) δ −75.03 (d, J=2.0 Hz), −107.59 (d, J=237.3 Hz), −121.91(d, J=237.1 Hz), −126.77 (dt, J=54.5, 15.0 Hz). ES/MS m/z: 415.6 [M+H].

Example 525.1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylethyl carbonate

1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(20 mg, 0.043 mmol) and DIPEA (0.05 mL) were combined in CHCl₃/water(3:1, 0.5 mL). Ethyl chloroformate (14 mg, 0.13 mmol) was added and thereaction was warmed to 40° C. After 45 minutes, the reaction wasconcentrated to dryness, treated with TFA (0.2 mL), the purified byRP-HPLC (MeCN/H₂O gradient with TFA modifier) affording1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylethyl carbonate. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.08 (d, J=1.2 Hz, 1H),7.95 (s, 1H), 7.59 (d, J=1.2 Hz, 1H), 6.61 (s, 1H), 5.49 (s, 1H),4.62-4.43 (m, 1H), 4.43-4.26 (m, 2H), 4.25-4.11 (m, 3H), 1.24 (t, J=7.1Hz, 3H). ES/MS m/z: 423.2 [M+H].

Example 526.1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylethylcarbamate

1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(20 mg, 0.043 mmol) and DIPEA (0.05 mL) were combined in DCM (0.5 mL).Ethyl isocyanate (10 mg, 0.14 mmol) was added and the reaction waswarmed to 40° C. After 45 minutes, the reaction was warmed to 50° C.After 1.5 hours, the reaction was concentrated to dryness, treated withTFA (0.2 mL), the purified by RP-HPLC (MeCN/H₂O gradient with TFAmodifier) affording1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylethylcarbamate. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.08 (d, J=1.2 Hz, 1H),7.94 (s, 1H), 7.58 (d, J=1.2 Hz, 1H), 6.60 (s, 1H), 5.55-5.28 (m, 1H),4.48 (s, 1H), 4.42-4.20 (m, 2H), 4.06 (s, 1H), 3.04 (q, J=7.2 Hz, 2H),1.02 (t, J=7.2 Hz, 3H). ES/MS m/z: 422.2 [M+H].

Examples 527 and 528.(S)-5-(8-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand(R)-5-(8-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwas separated by chiral SFC chromatography (AD-H column, 10% IPA-NH₃cosolvent) affording(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(peak 1), ES/MS m/z: 463.3 [M+H], and(R)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(peak 2), ES/MS m/z: 422.2 [M+H]. The separated enantiomers were treatedwith TFA and concentrated to provide(S)-5-(8-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.07 (d, J=1.2 Hz, 1H), 7.94 (s, 1H),7.58 (d, J=1.2 Hz, 1H), 6.59 (s, 1H), 4.52-4.17 (m, 3H), 4.11 (s, 1H),3.84 (s, 1H). ES/MS m/z: 351.2 [M+H]. And(R)-5-(8-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.07 (d, J=1.2 Hz, 1H), 7.95 (s, 1H),7.59 (d, J=1.2 Hz, 1H), 6.60 (s, 1H), 4.50-4.33 (m, 2H), 4.33-4.18 (m,1H), 4.10 (s, 1H), 3.84 (s, 1H). ES/MS m/z: 351.2 [M+H].

Example 529.(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 523, but replacing1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.¹H NMR (400 MHz, Methanol-d4) δ 8.58 (dt, J=2.8, 0.9 Hz, 1H), 8.16 (s,1H), 8.09-8.03 (m, 2H), 7.73 (d, J=1.5 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H),7.01 (s, 1H), 6.10-6.01 (m, 1H), 4.64-4.41 (m, 3H), 4.26 (d, J=12.2 Hz,1H). ES/MS m/z: 496.2 [M+H].

Example 530.(R)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 523, but replacing1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith(R)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.69 (dt, J=1.9, 1.0 Hz, 1H), 8.19 (dd,J=8.8, 2.6 Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.95 (s, 1H), 7.60 (d, J=1.2Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.65 (s, 1H), 6.18-5.90 (m, 1H),4.74-4.36 (m, 3H), 4.20 (d, J=12.8 Hz, 1H). ES/MS m/z: 496.1 [M+H].

Example 531.(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 529, but replacing2-fluoro-5-(trifluoromethyl)pyridine with2-chloro-5-(trifluoromethyl)pyrimidine. ¹H NMR (400 MHz, Methanol-d4) δ9.01 (d, J=0.9 Hz, 2H), 8.12 (s, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.65 (d,J=1.4 Hz, 1H), 6.90 (s, 1H), 6.16-5.94 (m, 1H), 4.67-4.43 (m, 3H), 4.37(d, J=12.9 Hz, 1H). ES/MS m/z: 497.1 [M+H].

Example 532.(R)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyrimidin-2-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionein the manner described for Example in the manner described for Example530, but replacing 2-fluoro-5-(trifluoromethyl)pyridine with2-chloro-5-(trifluoromethyl)pyrimidine. ¹H NMR (400 MHz, Methanol-d4) δ9.15-8.86 (m, 2H), 8.13 (s, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.65 (d, J=1.4Hz, 1H), 6.90 (s, 1H), 6.15-5.93 (m, 1H), 4.73-4.44 (m, 3H), 4.38 (d,J=13.0 Hz, 1H). ES/MS m/z: 497.2 [M+H].

Example 533.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(51 mg, 0.11 mmol) was combined with isopropylisocyanate (24 mg, 0.28mmol) and DIPEA (43 mg, 0.33 mmol) in DCM (0.5 mL) and stirred at 35° C.After 2 hours, additional isopropylisocyanate (24 mg, 0.28 mmol) wasadded, and the reaction was stirred overnight at 45° C. The next day,additional isopropylisocyanate (24 mg, 0.28 mmol) was added, and thereaction was stirred at 45° C. for 4 hours. The reaction was concentrateto dryness, treated with 0.3 mL TFA for 30 min, then diluted with MeCNand water and purified by RP-HPLC (MeCN/H₂O gradient with TFA modifier)affording(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate. ¹H NMR (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 8.08(d, J=1.5 Hz, 1H), 7.73 (d, J=1.5 Hz, 1H), 6.98 (s, 1H), 5.46 (s, 1H),4.58-4.24 (m, 3H), 4.13 (d, J=12.4 Hz, 1H), 3.76 (hept, J=6.6 Hz, 1H),1.17 (dd, J=8.1, 6.6 Hz, 6H). ES/MS m/z: 436.1 [M+H].

Example 534.(R)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate

(R)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate in the manner described for Example 526, butreplacing1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith(R)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-oland replacing ethylisocyanate with isopropylisocyanate. ¹H NMR (400 MHz,Methanol-d4) δ 8.12 (s, 1H), 8.01 (d, J=1.4 Hz, 1H), 7.65 (d, J=1.4 Hz,1H), 6.85 (s, 1H), 5.52-5.39 (m, 1H), 4.55-4.42 (m, 1H), 4.42-4.25 (m,2H), 4.14 (d, J=12.1 Hz, 1H), 3.76 (hept, J=6.6 Hz, 1H), 1.17 (t, J=7.1Hz, 6H). ES/MS m/z: 436.1 [M+H].

Examples 535.1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate

1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(14.5 mg, 0.0314 mmol) was combined with DIPEA (20 mg, 0.16 mmol) in DCM(0.5 mL) at 5° C. 4-Nitrophenyl chloroformate (8.9 mg, 0.044 mmol) wasadded and the reaction was allowed to warm to room temperature. After 3hours, 2,2,2-trifluoroethan-1-amine hydrochloride (8.5 mg, 0.063 mmol)was added and the reaction was stirred overnight at room temperature.The next day, aq NH₄Cl (1 mL) was added, and the mixture was stirred forminutes. The aqueous layer was removed, and the organic layer was rinsedwith aq NaHCO₃ (2×1 mL), dried, filtered, and concentrated. The residuewas treated with TFA (0.2 mL). After minutes, the reaction was dilutedwith MeCN and water and purified by RP-HPLC (MeCN/H₂O gradient with TFAmodifier) affording1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate. {¹H NMR (400 MHz, Methanol-d4) δ 8.20(s, 1H), 8.18-8.13 (m, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.12 (s, 1H), 5.56(s, 1H), 4.57-4.25 (m, 5H), 4.16 (d, J=12.4 Hz, 1H), 3.94-3.71 (m, 1H).ES/MS m/z: 476.1 [M+H].}

Example 536.1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl3,3-difluoroazetidine-1-carboxylate

1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl3,3-difluoroazetidine-1-carboxylate in the manner described for Example535, but replacing 2,2,2-trifluoroethan-1-amine hydrochloride with3,3-difluoroazetidine hydrochloride. ¹H NMR (400 MHz, Methanol-d4) δ8.20 (s, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.82 (d, J=1.7 Hz, 1H), 7.13 (s,1H), 5.63-5.46 (m, 1H), 4.56-4.30 (m, 7H), 4.18 (dt, J=12.5, 2.5 Hz,1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −78.14, −103.39 (h, J=12.0 Hz),−108.90-−111.06 (m), −124.19 (ddq, J=243.5, 8.2, 3.7 Hz). ES/MS m/z:470.1 [M+H].

Example 537.(S)-5-(8-(3,3-difluoro-4-(pyridin-2-yloxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(9 mg, 0.020 mmol), sodium hydride (60% dispersion in mineral oil, 2.2mg, 0.058 mmol), and 2-fluoropyridine (3.8 mg, 0.039 mmol) were combinedin NMP (0.1 mL) and stirred at 85° C. for 60 minutes. The reaction wascooled to rt, treated with TFA (0.3 mL), then diluted with water andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording(S)-5-(8-(3,3-difluoro-4-(pyridin-2-yloxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.24-8.17 (m, 3H), 7.89(d, J=1.9 Hz, 1H), 7.77 (ddd, J=8.3, 7.2, 2.0 Hz, 1H), 7.27 (s, 1H),7.08 (ddd, J=7.2, 5.1, 0.9 Hz, 1H), 6.93 (dt, J=8.3, 0.9 Hz, 1H),6.09-5.86 (m, 1H), 4.63-4.35 (m, 3H), 4.19 (dt, J=12.1, 2.6 Hz, 1H).ES/MS m/z: 428.1 [M+H].

Example 538 and 539.(R)-5-(8-(3,3-difluoro-4-(pyridin-2-yloxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-(3-fluoro-1H-pyrrol-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-(3-fluoro-1H-pyrrol-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(R)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(9 mg, 0.020 mmol), sodium hydride (60% dispersion in mineral oil, 2.2mg, 0.058 mmol), and 2-fluoropyridine (3.8 mg, 0.039 mmol) were combinedin NMP (0.1 mL) and stirred at 85° C. for 60 minutes. The reaction wascooled to rt, treated with TFA (0.3 mL), then diluted with water andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording(R)-5-(8-(3,3-difluoro-4-(pyridin-2-yloxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas a TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.38-8.14 (m, 3H), 7.90(d, J=1.9 Hz, 1H), 7.77-7.68 (m, 1H), 7.28 (s, 1H), 7.08 (ddd, J=7.2,5.1, 0.9 Hz, 1H), 6.93 (dt, J=8.3, 0.9 Hz, 1H), 6.04-5.91 (m, 1H),4.58-4.37 (m, 3H), 4.19 (d, J=11.8 Hz, 1H). ES/MS m/z: 428.1 [M+1-1].5-(8-(3-fluoro-1H-pyrrol-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas also isolated. ¹H NMR (400 MHz, DMSO-d6+D2O) δ 8.36 (d, J=1.2 Hz,1H), 8.18-8.10 (m, 1H), 8.08 (q, J=2.6 Hz, 1H), 8.05 (s, 1H), 7.84 (d,J=1.2 Hz, 1H), 7.81 (s, 1H), 6.43 (dd, J=3.5, 1.9 Hz, 1H). ¹⁹F NMR (377MHz, DMSO-d6) δ −74.18, −161.99-−162.10 (m). ES/MS m/z: 313.2 [M+H].

Example 540. (S)-2,2-difluoroethyl(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)carbonate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(7.8 mg, 0.017 mmol) and DIPEA (15 mg, 0.12 mmol) were combined inDCM/water (5:1, 0.2 mL). 2,2-Difluoroethyl chloroformate (11 mg, 0.076mmol) was added and the reaction was stirred at 35° C. for 1 hour.Additional 2,2-Difluoroethyl chloroformate (11 mg, 0.076 mmol) was addedand the reaction was stirred for 45 minutes. The reaction wasconcentrated, treated with TFA (0.3 mL), then diluted with water andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) to yield anover-acylated product. This product was treated with concentrated HCl (2drops), water (2 drops) and TFA (0.5 mL) at 70° C. overnight, thenrepurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) to yield(S)-2,2-difluoroethyl(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)carbonate as a TFA salt. ¹H NMR (400 MHz, Methanol-d4) δ 8.14 (s, 1H),8.05 (d, J=1.4 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 6.92 (s, 1H), 6.12 (tt,J=54.4, 3.6 Hz, 1H), 5.53 (td, J=5.5, 2.8 Hz, 1H), 4.63-4.22 (m, 6H).ES/MS m/z: 459.2 [M+H].

Example 541.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl) carbonate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(7.8 mg, 0.017 mmol) and DIPEA (15 mg, 0.12 mmol) were combined inDCM/water (5:1, 0.2 mL). 2,2,2-trifluoroethyl chloroformate (11 mg,0.076 mmol) was added and the reaction was stirred at 35° C. for 1 hour.Additional 2,2,2-trifluoroethyl chloroformate (11 mg, 0.076 mmol) wasadded and the reaction was stirred for 45 minutes. The reaction wasconcentrated, treated with TFA (0.3 mL), then diluted with water andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) to yield anover-acylated product. This product was treated with concentrated HCl (2drops), water (2 drops) and TFA (0.5 mL) at 70° C. overnight, thenrepurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) to yield(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl) carbonate as a TFA salt. ¹H NMR (400 MHz,Methanol-d4) δ 8.14 (s, 1H), 8.05 (d, J=1.4 Hz, 1H), 7.69 (d, J=1.4 Hz,1H), 6.92 (s, 1H), 5.64-5.49 (m, 1H), 4.84-4.71 (m, 2H), 4.61-4.49 (m,1H), 4.49-4.23 (m, 3H). ES/MS m/z: 477.2 [M+H].

Example 542. (R)-2,2-difluoroethyl(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)carbonate

(R)-2,2-difluoroethyl(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)carbonate in the manner described for Example 540, but replacing(5)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith(R)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.¹H NMR (400 MHz, Methanol-d4) δ 8.13 (s, 1H), 8.03 (d, J=1.4 Hz, 1H),7.67 (d, J=1.4 Hz, 1H), 6.90 (s, 1H), 6.12 (tt, J=54.5, 3.6 Hz, 1H),−5.48 (m, 1H), 4.64-4.23 (m, 6H). ES/MS m/z: 459.2 [M+H].

Example 543.(R)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl) carbonate

(R)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl) carbonate in the manner described for Example541, but replacing(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-olwith(R)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.¹H NMR (400 MHz, Methanol-d4) δ 8.16 (s, 1H), 8.08 (d, J=1.5 Hz, 1H),7.73 (d, J=1.5 Hz, 1H), 6.98 (s, 1H), 5.57 (td, J=5.4, 2.7 Hz, 1H),4.83-4.71 (m, 2H), 4.61-4.48 (m, 1H), 4.48-4.26 (m, 3H). ¹⁹F NMR (376MHz, Methanol-d4) δ −74.94-−77.33 (m), −78.08, −107.67-−111.41 (m),−124.29 (d, J=245.9 Hz). ES/MS m/z: 477.1 [M+H].

Example 544.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yltert-butylcarbamate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(7 mg, 0.015 mmol) was combined with tert-butylisocyanate (30 mg, 0.30mmol) and DIPEA (59 mg, 0.45 mmol) in 1,2-DCE (0.5 mL) and stirred at60° C. overnight. The next day, the reaction was warmed to 70° C. andstirred an addition 6 hours. The reaction was concentrated to dryness,treated with 0.3 mL TFA for 30 min, then diluted with MeCN and water andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yltert-butylcarbamate. ¹H NMR (400 MHz, Methanol-d4) δ 8.14 (s, 1H), 8.06(d, J=1.5 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 6.94 (s, 1H), 5.42 (s, 1H),4.56-4.25 (m, 3H), 4.12 (d, J=12.3 Hz, 1H), 1.32 (s, 9H). ES/MS m/z:450.1 [M+H].

Example 545.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate

(S)-1-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(50 mg, 0.11 mmol) was combined with DIPEA (140 mg, 1.1 mmol) in DCM(0.5 mL) at rt. 4-Nitrophenyl chloroformate (52 mg, 0.26 mmol) was addedand the reaction was stirred for 2 hours. 2,2,2-trifluoroethan-1-aminehydrochloride (73 mg, 0.54 mmol) was added and the reaction was stirredovernight at room temperature. The next day, aq NH₄Cl (1 mL) was added,and the mixture was stirred for 10 minutes. The aqueous layer wasremoved, and the organic layer was rinsed with aq NaHCO₃ (2×1 mL),dried, filtered, and concentrated. The residue was treated with TFA (0.2mL). After 10 minutes, the reaction was diluted with MeCN and water andpurified by RP-HPLC (MeCN/H₂O gradient with TFA modifier) affording(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(2,2,2-trifluoroethyl)carbamate. ¹H NMR (400 MHz, Methanol-d4) δ8.21-8.11 (m, 2H), 8.05 (d, J=1.5 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 6.92(s, 1H), 5.64-5.37 (m, 1H), 4.57-4.44 (m, 1H), 4.44-4.27 (m, 2H), 4.18(d, J=12.5 Hz, 1H), 3.91-3.77 (m, 2H). ES/MS m/z: 476.2 [M+H].

Example 546.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((R)-1,1,1-trifluoropropan-2-yl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((R)-1,1,1-trifluoropropan-2-yl)carbamate in the manner described forExample 545, but replacing 2,2,2-trifluoroethan-1-amine hydrochloridewith (R)-1,1,1-trifluoropropan-2-amine. ¹H NMR (400 MHz, Methanol-d4) δ8.20-8.08 (m, 2H), 8.02 (d, J=1.4 Hz, 1H), 7.66 (d, J=1.4 Hz, 1H), 6.87(s, 1H), 5.49 (s, 1H), 4.63-4.46 (m, 1H), 4.46-4.26 (m, 2H), 4.19 (d,J=12.8 Hz, 1H), 1.32 (d, J=7.2 Hz, 3H). ES/MS m/z: 490.2 [M+H].

Example 547.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((S)-1,1,1-trifluoropropan-2-yl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((S)-1,1,1-trifluoropropan-2-yl)carbamate in the manner described forExample 545, but replacing 2,2,2-trifluoroethan-1-amine hydrochloridewith (S)-1,1,1-trifluoropropan-2-amine. ¹H NMR (400 MHz, Methanol-d4) δ8.18 (s, 1H), 8.15 (d, J=9.2 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 7.79 (d,J=1.7 Hz, 1H), 7.08 (s, 1H), 5.54 (s, 1H), 4.59-4.27 (m, 3H), 4.15 (d,J=12.1 Hz, 1H), 1.35 (d, J=7.1 Hz, 3H). ES/MS m/z: 490.2 [M+H].

Example 548.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((R)-1-methoxypropan-2-yl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((R)-1-methoxypropan-2-yl)carbamate in the manner described for Example545, but replacing 2,2,2-trifluoroethan-1-amine hydrochloride with(R)-1-methoxypropan-2-amine hydrochloride. ¹H NMR (400 MHz,Methanol-d4+CF₃COOH) δ 8.33 (d, J=2.2 Hz, 1H), 8.31 (s, 1H), 8.05 (d,J=2.2 Hz, 1H), 7.52 (s, 1H), 5.52 (s, 2H), 4.37 (td, J=18.5, 16.7, 6.1Hz, 3H), 4.10 (d, J=11.7 Hz, 1H), 3.84 (h, J=6.3 Hz, 1H), 3.36 (s, 3H),1.14 (d, J=6.8 Hz, 3H). ES/MS m/z: 466.2 [M+H].

Example 549.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((S)-1-methoxypropan-2-yl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl((S)-1-methoxypropan-2-yl)carbamate in the manner described for Example545, but replacing 2,2,2-trifluoroethan-1-amine hydrochloride with(S)-1-methoxypropan-2-amine hydrochloride. ¹H NMR (400 MHz,Methanol-d4+CF₃COOH) δ 8.33 (d, J=2.2 Hz, 1H), 8.31 (s, 1H), 8.05 (d,J=2.2 Hz, 1H), 7.52 (s, 1H), 5.52 (s, 2H), 4.37 (td, J=18.5, 16.7, 6.1Hz, 3H), 4.10 (d, J=11.7 Hz, 1H), 3.84 (h, J=6.3 Hz, 1H), 3.36 (s, 3H),1.14 (d, J=6.8 Hz, 3H). ES/MS m/z: 466.2 [M+H].

Example 550.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(1,1-difluoropropan-2-yl)carbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(1,1-difluoropropan-2-yl)carbamate in the manner described for Example545, but replacing 2,2,2-trifluoroethan-1-amine hydrochloride with1,1-difluoropropan-2-amine hydrochloride. ¹H NMR (400 MHz,Methanol-d4+CF₃COOH) δ 8.33 (d, J=2.1 Hz, 1H), 8.30 (s, 1H), 8.03 (d,J=2.1 Hz, 1H), 7.46 (s, 1H), 5.83 (tdd, J=56.1, 9.1, 2.8 Hz, 1H), 5.56(s, 1H), 4.49-4.29 (m, 3H), 4.20-4.09 (m, 1H), 4.06-3.93 (m, 1H), 1.23(dd, J=10.3, 7.0 Hz, 3H). ES/MS m/z: 472.2 [M+H].

Example 551.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylbicyclo[1.1.1]pentan-1-ylcarbamate

(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ylbicyclo[1.1.1]pentan-1-ylcarbamatein the manner described for Example 545, but replacing2,2,2-trifluoroethan-1-amine hydrochloride withbicyclo[1.1.1]pentan-1-amine hydrochloride. ¹H NMR (400 MHz,Methanol-d4) δ 8.13 (s, 1H), 8.03 (d, J=1.4 Hz, 1H), 7.67 (d, J=1.4 Hz,1H), 6.89 (s, 1H), 5.43 (s, 1H), 4.59-4.43 (m, 1H), 4.42-4.24 (m, 2H),4.12 (d, J=12.6 Hz, 1H), 2.41 (s, 1H), 2.05 (s, 6H). ES/MS m/z: 460.1[M+H].

Example 552.5-(8-((1S,3S)-3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,3S)-3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,3S)-3-(3,4-difluorophenyl)-2,2-difluorocyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 418.12 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.63-11.50 (m, 2H), 8.36 (d, J=1.3 Hz, 1H), 8.05 (d, J=6.1 Hz, 1H),7.86 (d, J=1.3 Hz, 1H), 7.78 (s, 1H), 7.71-7.61 (m, 1H), 7.55-7.45 (m,1H), 7.41-7.34 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −75.25,−132.32-−133.28 (m), —133.74-−134.93 (m), −138.59-−139.01 (m),−140.38-−140.69 (m).

Example 553.2-chloro-5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

2-chloro-5-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-chloro-5-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile.ES/MS m/z: 405.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.60-11.50 (m,2H), 8.35 (s, 1H), 8.03 (d, J=6.0 Hz, 1H), 7.92-7.86 (m, 2H), 7.72-7.59(m, 3H), 2.95-2.85 (m, 1H), 2.85-2.74 (m, 1H), 2.19-2.08 (m, 1H),1.93-1.80 (m, 1H).

Example 554.5-(8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 414.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62-11.52 (m,2H), 8.38 (d, J=1.5 Hz, 1H), 8.05 (d, J=6.1 Hz, 1H), 7.97-7.91 (m, 1H),7.70-7.62 (m, 3H), 7.51-7.44 (m, 2H), 2.94-2.86 (m, 1H), 2.86-2.78 (m,1H), 2.16-2.04 (m, 1H), 1.91-1.80 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−61.27, −75.21.

Example 555.5-(8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(2-chlorophenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 380.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.38-8.33 (m, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 8.05 (s,1H), 7.46-7.40 (m, 1H), 7.36-7.23 (m, 3H), 2.99-2.86 (m, 1H), 2.62-2.52(m, 1H), 2.06-1.96 (m, 1H), 1.95-1.85 (m, 1H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.75.

Example 556.5-(8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 412.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.40 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.09 (d, J=2.0 Hz,1H), 8.04 (s, 1H), 7.38-7.29 (m, 2H), 7.18-7.09 (m, 2H), 6.81 (t, J=74.1Hz, 1H), 2.80-2.66 (m, 2H), 1.98-1.88 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.85, −83.91 (d, J=74.2 Hz).

Example 557.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,6-difluorobenzonitrile.ES/MS m/z: 407.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.40 (d, J=1.9Hz, 1H), 8.30 (s, 1H), 8.10 (d, J=1.9 Hz, 1H), 8.06 (s, 1H), 7.25-7.15(m, 2H), 2.92-2.75 (m, 2H), 2.12-1.94 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.95, −107.99 (d, J=9.6 Hz).

Example 558.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,3-difluorobenzonitrile.ES/MS m/z: 407.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.39 (d, J=2.0Hz, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.62-7.53(m, 1H), 7.28-7.19 (m, 1H), 2.99-2.80 (m, 2H), 2.13-1.95 (m, 2H). ¹⁹FNMR (376 MHz, Methanol-d4) δ −77.96, −135.73-−135.87 (m),−143.81-−144.01 (m).

Example 559.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methoxybenzonitrile.ES/MS m/z: 401.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.39 (d, J=2.0Hz, 1H), 8.30 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 7.57 (d,J=8.0 Hz, 1H), 7.11-7.05 (m, 1H), 7.00-6.92 (m, 1H), 3.97 (s, 3H),2.88-2.75 (m, 2H), 2.03-1.96 (m, 2H).

Example 560.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzonitrile.ES/MS m/z: 385.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J=1.9Hz, 1H), 8.27 (s, 1H), 8.03 (d, J=1.9 Hz, 1H), 7.98 (s, 1H), 7.62 (d,J=8.0 Hz, 1H), 7.33 (s, 1H), 7.27-7.20 (m, 1H), 2.86-2.70 (m, 2H), 2.53(s, 3H), 2.03-1.89 (m, 2H).

Example 561.5-(8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-(difluoromethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 412.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J=1.9Hz, 1H), 8.28 (s, 1H), 8.05 (d, J=1.9 Hz, 1H), 7.99 (s, 1H), 7.35-7.27(m, 2H), 7.16-7.08 (m, 2H), 6.79 (t, J=74.1 Hz, 1H), 2.79-2.65 (m, 2H),1.95-1.85 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.78, −83.90 (d,J=74.2 Hz).

Example 562.5-(8-((1S,2S)-2-(2-(trifluoromethyl)benzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(2-(trifluoromethyl)benzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(trifluoromethyl)benzo[d]thiazole.ES/MS m/z: 471.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.32 (d, J=1.8Hz, 1H), 8.26 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H),7.98 (d, J=1.8 Hz, 1H), 7.95 (s, 1H), 7.61 (dd, J=8.6, 1.8 Hz, 1H),2.96-2.83 (m, 2H), 2.10-1.97 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−63.97, −77.76.

Example 563.2-cyclopropyl-4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

2-cyclopropyl-4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-cyclopropyl-4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile.ES/MS m/z: 411.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J=2.0Hz, 1H), 8.28 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.61 (d,J=8.1 Hz, 1H), 7.18 (dd, J=8.1, 1.7 Hz, 1H), 6.97 (d, J=1.7 Hz, 1H),2.82-2.71 (m, 2H), 2.29-2.20 (m, 1H), 2.01-1.88 (m, 2H), 1.22-1.09 (m,2H), 0.94-0.80 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.90.

Example 564.5-(8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 444.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.34 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J=1.9 Hz,1H), 7.95 (s, 1H), 4.52 (q, J=8.5 Hz, 2H), 2.76-2.61 (m, 2H), 1.87 (t,J=7.5 Hz, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −76.35 (t, J=8.5 Hz),−77.73.

Example 565.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile.ES/MS m/z: 407.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.60-11.50 (m,2H), 8.35 (s, 1H), 8.02 (d, J=6.1 Hz, 1H), 7.95 (dd, J=9.4, 5.4 Hz, 1H),7.88 (bs, 1H), 7.66 (s, 1H), 7.53 (dd, J=10.2, 6.0 Hz, 1H), 3.14-3.03(m, 1H), 2.96-2.87 (m, 1H), 2.28-2.19 (m, 1H), 2.01-1.90 (m, 1H). ¹⁹FNMR (376 MHz, DMSO-d6) δ −113.84-−113.99 (m), −123.11-−123.32 (m).

Example 566.2-chloro-4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

2-chloro-4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-chloro-4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile.ES/MS m/z: 405.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J=1.8Hz, 1H), 8.28 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.98 (s, 1H), 7.78 (d,J=8.1 Hz, 1H), 7.59 (d, J=1.7 Hz, 1H), 7.41 (dd, J=8.1, 1.7 Hz, 1H),2.92-2.76 (m, 2H), 2.10-1.93 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−77.86.

Example 567.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluoro-6-methylbenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluoro-6-methylbenzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-fluoro-6-methylbenzonitrile.ES/MS m/z: 403.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.38 (d, J=2.0Hz, 1H), 8.29 (s, 1H), 8.07 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.18 (s,1H), 7.09 (d, J=10.2 Hz, 1H), 2.87-2.80 (m, 1H), 2.79-2.72 (m, 1H), 2.54(s, 3H), 2.05-1.91 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.90,−110.59 (d, J=10.3 Hz).

Example 568.5-(8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(6-chloropyridin-3-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 381.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.42 (d, J=2.1 Hz, 1H), 8.36 (d, J=2.6 Hz, 1H), 8.31 (s,1H), 8.14 (d, J=2.1 Hz, 1H), 8.11 (s, 1H), 7.71 (dd, J=8.3, 2.6 Hz, 1H),7.45 (d, J=8.3 Hz, 1H), 2.82-2.71 (m, 2H), 2.03-1.91 (m, 2H).

Example 569.5-(8-(6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 339.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H),8.24 (d, J=2.1 Hz, 1H), 7.96 (d, J=2.1 Hz, 1H), 7.31 (s, 1H), 3.90-3.82(m, 4H), 2.26-2.14 (m, 4H), 2.16-2.00 (m, 4H).

Example 570.5-(8-((1S,2S)-2-(2-methylbenzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2-methylbenzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole(racemic mixture). ES/MS m/z: 417.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.38 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 8.07 (d, J=2.0 Hz,1H), 8.06 (s, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.41(dd, J=8.5, 1.8 Hz, 1H), 2.90-2.84 (m, 1H), 2.83 (s, 3H), 2.81-2.74 (m,1H), 2.04-1.95 (m, 2H).

Example 571.5-(8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(2,2-difluoro-6-azaspiro[3.4]octan-6-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 375.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.25 (s, 1H),8.23 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.28 (s, 1H), 3.98 (s,2H), 3.93 (d, J=6.8 Hz, 2H), 2.85-2.61 (m, 4H), 2.30 (t, J=6.8 Hz, 2H).¹⁹F NMR (376 MHz, Methanol-d4) δ −91.22-−93.35 (m).

Example 572.5-(8-(3-(methoxymethyl)-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(methoxymethyl)-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(methoxymethyl)-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 357.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.21 (s, 1H),8.16 (d, J=2.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.19 (s, 1H), 3.94 (t,J=7.2 Hz, 2H), 3.85 (d, J=10.4 Hz, 1H), 3.58 (d, J=10.4 Hz, 1H), 3.38(s, 3H), 3.36 (s, 2H), 2.20-2.11 (m, 1H), 1.96-1.83 (m, 1H), 1.23 (s,3H).

Example 573.4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile

4-((1S,2S)-2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrilewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith4-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2,5-difluorobenzonitrile.ES/MS m/z: 425.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),7.68 (s, 1H), 7.57 (dd, J=9.2, 5.3 Hz, 1H), 7.47 (d, J=6.7 Hz, 1H), 7.31(dd, J=9.8, 5.9 Hz, 1H), 3.01-2.93 (m, 1H), 2.92-2.83 (m, 1H), 2.17-2.08(m, 1H), 1.93-1.85 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −78.16,−115.24-−115.40 (m), −124.37-−124.55 (m), −157.10 (d, J=6.7 Hz).

Example 574.5-(8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-(2,2-difluoroethoxy)phenyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 426.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.35 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.04 (d, J=2.0 Hz,1H), 7.96 (s, 1H), 6.15 (tt, J=55.0, 3.8 Hz, 1H), 4.21 (td, J=13.8, 3.8Hz, 2H), 2.73-2.61 (m, 2H), 1.90-1.82 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.73, −128.19 (dt, J=54.9, 13.8 Hz).

Example 575.5-(8-(6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(6,6-difluoro-3-azabicyclo[3.1.1]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-6,6-difluoro-3-azabicyclo[3.1.1]heptane.ES/MS m/z: 361.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H),8.16 (s, 1H), 7.84 (s, 1H), 7.28 (s, 1H), 4.57-4.46 (m, 1H), 4.38-4.24(m, 1H), 3.79-3.67 (m, 2H), 3.67-3.54 (m, 1H), 3.17-3.06 (m, 1H),3.02-2.85 (m, 1H), 2.55-2.37 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−95.74-−98.79 (m).

Example 576.5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 381.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.54-8.50 (m, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.32 (s, 1H),8.13 (s, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.77 (dd, J=8.4, 2.5 Hz, 1H), 7.46(dd, J=8.4, Hz, 1H), 3.09-2.98 (m, 1H), 2.93-2.86 (m, 1H), 2.16-2.08 (m,1H), 1.96-1.88 (m, 1H).

Example 577.5-(8-(3-cyclopropylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-cyclopropylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-cyclopropylpyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 339.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1H),8.17-8.09 (m, 1H), 7.86-7.78 (m, 1H), 7.14 (s, 1H), 4.11-3.90 (m, 2H),3.87-3.74 (m, 1H), 3.70-3.60 (m, 1H), 2.34-2.20 (m, 1H), 2.02-1.90 (m,1H), 1.88-1.73 (m, 1H), 0.92-0.76 (m, 1H), 0.62-0.51 (m, 2H), 0.32-0.22(m, 2H).

Example 578.5-(8-(3-(3,3-difluorocyclobutyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(3,3-difluorocyclobutyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-(3,3-difluorocyclobutyl)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 389.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.24 (s, 1H),8.21 (s, 1H), 7.91 (s, 1H), 7.24 (s, 1H), 4.12-3.77 (m, 3H), 3.57-3.48(m, 1H), 2.84-2.68 (m, 2H), 2.60-2.51 (m, 1H), 2.50-2.34 (m, 2H),2.35-2.21 (m, 2H), 1.93-1.80 (m, 1H). ¹⁹F NMR (377 MHz, Methanol-d4) δ−84.25-−85.21 (m), −96.91-−98.31 (m).

Example 579.5-(8-(1-fluoro-3-azabicyclo[3.1.1]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(1-fluoro-3-azabicyclo[3.1.1]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1-fluoro-3-azabicyclo[3.1.1]heptane.ES/MS m/z: 342.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.23 (s, 1H),8.19 (d, J=1.9 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.33 (s, 1H), 4.15 (d,J=3.8 Hz, 2H), 3.99-3.91 (m, 2H), 2.84-2.68 (m, 1H), 2.53-2.41 (m, 2H),2.08-1.91 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −143.44-−143.86 (m).

Example 580.5-(3-fluoro-8-((1S,2S)-2-(2-methylbenzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(3-fluoro-8-((1S,2S)-2-(2-methylbenzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-methylbenzo[d]thiazole(racemic mixture). ES/MS m/z: 435.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.56-11.49 (m, 1H), 8.03 (d, J=6.4 Hz, 1H), 7.93 (d, J=1.8 Hz, 1H),7.83 (d, J=8.4 Hz, 1H), 7.54 (d, J=7.1 Hz, 1H), 7.49 (s, 1H), 7.37 (dd,J=8.4, 1.8 Hz, 1H), 2.99-2.90 (m, 1H), 2.78 (s, 3H), 2.82-2.71 (m, 1H),2.19-2.10 (m, 1H), 1.87-1.79 (m, 1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−155.60 (d, J=7.1 Hz).

Example 581.5-(8-((1S,2S)-2-(benzo[d]thiazol-6-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(benzo[d]thiazol-6-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazole(racemic mixture). ES/MS m/z: 421.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.59-11.50 (m, 2H), 9.33 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 8.05-7.96 (m,2H), 7.57 (d, J=7.0 Hz, 1H), 7.51 (s, 1H), 7.44 (dd, J=8.5, 1.8 Hz, 1H),3.03-2.93 (m, 1H), 2.82-2.73 (m, 1H), 2.23-2.11 (m, 1H), 1.91-1.81 (m,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −155.52 (d, J=7.0 Hz).

Example 582.5-(8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith 6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-fluoro-(racemicmixture). ES/MS m/z: 433.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.71(s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.02-7.97 (m, 1H), 7.97-7.90 (m,2H), 3.22-3.14 (m, 2H), 2.24-2.14 (m, 1H), 2.11-2.02 (m, 1H). ¹⁹F NMR(376 MHz, Methanol-d4) δ −64.00, −77.76, −129.81-−130.33 (m).

Example 583.5-(8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 417.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.37 (d, J=2.0 Hz, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.69(dd, J=9.4, 2.0 Hz, 1H), 7.51 (d, J=6.6 Hz, 1H), 3.16-2.99 (m, 2H),2.11-1.97 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −78.15, −129.11 (d,J=9.2 Hz), −156.91 (d, J=6.8 Hz).

Example 584.5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 399.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J=2.5Hz, 1H), 8.21 (s, 1H), 7.74 (dd, J=8.4, 2.5 Hz, 1H), 7.70 (s, 1H),7.53-7.46 (m, 1H), 7.40 (d, J=8.4 Hz, 1H), 3.06-2.97 (m, 1H), 2.94-2.86(m, 1H), 2.05-1.92 (m, 2H).

Example 585.5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 381.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J=2.5Hz, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 8.10 (d,J=2.0 Hz, 1H), 7.76 (dd, J=8.3, 2.5 Hz, 1H), 7.47-7.41 (m, 1H),3.05-2.96 (m, 1H), 2.92-2.81 (m, 1H), 2.14-2.06 (m, 1H), 1.96-1.85 (m,1H).

Example 586.5-(8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 399.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.40 (d, J=2.0Hz, 2H), 8.30 (s, 1H), 8.14 (s, 1H), 8.09 (d, J=2.0 Hz, 1H), 7.74 (dd,J=9.4, 2.0 Hz, 1H), 3.12-3.01 (m, 2H), 2.19-2.10 (m, 1H), 2.01-1.92 (m,1H).

Example 587.5-(8-(8,8-difluoro-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(8,8-difluoro-2-azaspiro[4.5]decan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-8,8-difluoro-2-azaspiro[4.5]decane.ES/MS m/z: 403.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.15 (s, 1H),8.09-8.05 (m, 1H), 7.79-7.71 (m, 1H), 6.98 (s, 1H), 3.99-3.87 (m, 2H),3.87-3.77 (m, 2H), 2.12-1.91 (m, 6H), 1.85-1.70 (m, 4H). ¹⁹F NMR (376MHz, Methanol-d4) δ −97.66-−101.57 (m).

Example 588.5-(8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloro-3-fluoropyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 417.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.38 (d, J=2.0Hz, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.69 (dd, J=9.4, 2.0 Hz, 1H), 7.50(d, J=6.6 Hz, 1H), 3.15-3.01 (m, 2H), 2.11-1.99 (m, 2H).

Example 589.5-(8-((1S,2S)-2-(2-(difluoromethyl)benzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2-(difluoromethyl)benzo[d]thiazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith2-(difluoromethyl)-6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzo[d]thiazole(racemic mixture). ES/MS m/z: 453.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.36 (d, J=1.9 Hz, 1H), 8.29 (s, 1H), 8.12-7.98 (m, 4H),7.54 (dd, J=8.6, 1.8 Hz, 1H), 7.13 (t, J=54.3 Hz, 1H), 2.97-2.88 (m,1H), 2.87-2.79 (m, 1H), 2.08-1.97 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −77.80, −112.83 (d, J=54.7 Hz).

Example 590.5-(8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-(2,2-difluoroethoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 427.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.36 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.9 Hz, 1H), 8.28 (s,1H), 8.05-8.01 (m, 2H), 7.52-7.39 (m, 2H), 6.20 (tt, J=54.7, 3.7 Hz,1H), 4.34 (td, J=13.8, 3.7 Hz, 2H), 2.09-2.02 (m, 1H), 1.95-1.86 (m,1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.81, −128.44 (dt, J=54.8, 13.8Hz).

Example 591.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 469.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 9.38 (s, 1H), 8.66 (s, 1H), 8.40 (d, J=1.9 Hz, 1H), 8.32(s, 1H), 8.14 (s, 1H), 8.13 (s, 1H), 8.08 (d, J=1.9 Hz, 1H), 5.44 (q,J=8.6 Hz, 2H), 3.13 (t, J=7.5 Hz, 2H), 2.34-2.22 (m, 1H), 2.22-2.12 (m,1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.77 (t, J=8.6 Hz), —78.01.

Example 592.5-(8-(3-((1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-((1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-(3-((1H-1,2,3-triazol-1-yl)methyl)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 380.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H),8.19 (d, J=2.0 Hz, 1H), 8.11-8.07 (m, 1H), 7.89 (d, J=2.0 Hz, 1H),7.79-7.76 (m, 1H), 7.23 (s, 1H), 4.65 (d, J=7.2 Hz, 2H), 4.06-3.94 (m,2H), 3.94-3.83 (m, 1H), 3.79-3.65 (m, 1H), 3.16-3.02 (m, 1H), 2.35-2.21(m, 1H), 2.07-1.93 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.95.

Example 593.5-(8-(3-(prop-2-yn-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-(prop-2-yn-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-(3-(prop-2-yn-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 337.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.18 (s, 1H),8.11 (d, J=1.8 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.10 (s, 1H), 4.11-3.94(m, 2H), 3.93-3.80 (m, 1H), 3.71-3.61 (m, 1H), 2.73-2.56 (m, 1H),2.50-2.43 (m, 2H), 2.38 (t, J=2.6 Hz, 1H), 2.35-2.25 (m, 1H), 2.07-1.96(m, 1H).

Example 594.5-(8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 486.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J=1.9Hz, 1H), 8.29 (s, 1H), 8.14 (d, J=2.3 Hz, 1H), 8.09 (s, 1H), 8.06 (d,J=1.9 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 6.0 Hz, 1H),5.22 (q, J=8.5 Hz, 2H), 3.09-2.99 (m, 1H), 2.91-2.80 (m, 1H), 2.08-1.96(m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −73.69-−73.79 (m), −77.83,−143.15-−143.26 (m).

Example 595.5-(8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 486.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J=1.9Hz, 1H), 8.28 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 8.03 (d, J=1.9 Hz,1H), 7.63 (d, J=5.8 Hz, 1H), 7.49 (d, J=10.0 Hz, 1H), 5.24 (q, J=8.7 Hz,2H), 2.99-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.16-2.05 (m, 1H), 2.02-1.94(m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.97 (t, J=8.7 Hz), −77.81,−128.41 (dd, J=10.0, 5.8 Hz).

Example 596.5-(8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 486.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J=1.9Hz, 1H), 8.29 (s, 1H), 8.16-8.14 (m, 1H), 8.05 (d, J=1.9 Hz, 1H), 8.03(s, 1H), 7.45 (s, 1H), 6.90-6.84 (m, 1H), 5.22 (q, J=8.7 Hz, 2H),2.98-2.88 (m, 1H), 2.87-2.78 (m, 1H), 2.08-1.95 (m, 2H). ¹⁹F NMR (376MHz, Methanol-d4) δ −72.90 (t, J=8.6 Hz), −77.85, −120.87 (d, J=11.0Hz).

Example 597.5-(8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloro-4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.41 (s, 1H), 8.39 (d, J=2.0 Hz, 1H), 8.30 (s, 1H), 8.09(s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.24 (s, 1H), 4.42-4.32 (m, 1H),4.32-4.20 (m, 1H), 3.07-2.96 (m, 1H), 2.90-2.82 (m, 1H), 2.32-2.17 (m,1H), 2.16-2.07 (m, 1H), 1.98-1.90 (m, 1H), 1.77-1.64 (m, 1H), 1.50-1.37(m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.97, −131.12-−131.83 (m),—145.29-−145.94 (m).

Example 598.5-(8-((1S,2S)-2-(2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydroquinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydroquinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)quinolin-2(1H)-one(racemic mixture). ES/MS m/z: 495.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.41 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.13-8.07 (m, 2H),7.96 (d, J=9.5 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.58 (s, 1H), 7.29-7.18(m, 1H), 6.67 (d, J=9.5 Hz, 1H), 5.34-5.10 (m, 2H), 2.96-2.88 (m, 1H),2.88-2.81 (m, 1H), 2.10-1.98 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−69.85 (t, J=8.7 Hz).

Example 599.5-(8-((1S,2S)-2-(2-(2,2,2-trifluoroethoxy)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2-(2,2,2-trifluoroethoxy)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(2,2,2-trifluoroethoxy)quinoline(racemic mixture). ES/MS m/z: 495.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.36-8.32 (m, 1H), 8.28 (s, 1H), 8.20 (d, J=8.8 Hz, 1H),8.03-7.99 (m, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.75-7.72 (m, 1H), 7.40 (dd,J=8.4, 1.8 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 5.08-4.97 (m, 2H), 2.94-2.86(m, 2H), 2.09-1.96 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −75.96 (t,J=8.7 Hz), —77.74.

Example 600.5-(8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(5-chloro-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 479.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.43 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.11(s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.30 (s, 1H), 4.84-4.75 (m, 2H),3.07-2.98 (m, 1H), 2.92-2.78 (m, 1H), 2.16-2.05 (m, 1H), 1.96-1.86 (m,1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −76.13 (t, J=8.2 Hz), −77.93.

Example 601.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine(racemic mixture). ES/MS m/z: 469.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.36 (d, J=1.9 Hz, 1H), 8.29 (s, 1H), 8.14 (d, J=8.2 Hz,1H), 8.14 (s, 1H), 8.08 (s, 1H), 8.03 (d, J=1.9 Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 5.35-5.09 (m, 2H), 3.21-3.13 (m, 1H), 3.09-3.00 (m, 1H),2.29-2.20 (m, 1H), 2.00-1.91 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−72.76 (t, J=8.8 Hz), −77.73.

Example 602.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine(racemic mixture). ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.21 (s, 1H), 8.12 (s, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.71(s, 1H), 7.48 (d, J=6.6 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 5.36-5.08 (m,2H), 3.27-3.18 (m, 1H), 3.12-3.04 (m, 1H), 2.20-2.12 (m, 1H), 2.07-1.99(m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.81 (t, J=8.8 Hz), −78.13,−157.05 (d, J=6.6 Hz).

Example 603.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 536.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.33 (d, J=1.8 Hz, 1H), 8.27 (s, 1H), 8.00 (d, J=1.8 Hz,1H), 7.97 (s, 1H), 7.81 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 7.40 (dd,J=8.6, 1.6 Hz, 1H), 5.31 (q, J=8.4 Hz, 2H), 3.00-2.90 (m, 1H), 2.88-2.78(m, 1H), 2.08-1.95 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −63.38 (q,J=5.1 Hz), −72.15-−72.27 (m), −77.80.

Example 604.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 487.00 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 9.37 (s, 1H), 8.68 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H),7.75 (s, 1H), 7.45 (d, J=6.8 Hz, 1H), 5.46 (q, J=8.6 Hz, 2H), 3.29-3.20(m, 1H), 3.11-3.03 (m, 1H), 2.35-2.26 (m, 1H), 2.19-2.09 (m, 1H). ¹⁹FNMR (376 MHz, Methanol-d4) δ −72.77 (t, J=8.6 Hz), −77.92, −157.20 (d,J=7.0 Hz).

Example 605.5-(8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 468.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.41 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.27 (s, 1H), 7.99(d, J=1.8 Hz, 1H), 7.94 (s, 1H), 7.74-7.68 (m, 2H), 6.99 (d, J=9.6 Hz,1H), 4.31 (q, J=10.1 Hz, 2H), 2.92-2.70 (m, 2H), 2.01-1.88 (m, 2H). ¹⁹FNMR (376 MHz, Methanol-d4) δ −66.51 (t, J=10.1 Hz), −77.93.

Example 606.5-(8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 518.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.40 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.08 (d, J=2.0 Hz,1H), 8.07 (s, 1H), 7.75-7.68 (m, 2H), 7.51-7.46 (m, 1H), 7.21 (t, J=52.1Hz, 1H), 5.31 (q, J=8.5 Hz, 2H), 2.97-2.89 (m, 1H), 2.84-2.75 (m, 1H),2.09-1.92 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.28-−72.39 (m),−77.83, −117.55-−117.86 (m).

Example 607.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 536.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.34 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.99 (s, 1H), 7.82 (d,J=8.6 Hz, 1H), 7.73 (s, 1H), 7.40-7.29 (m, 1H), 5.34 (q, J=8.6 Hz, 2H),3.00-2.91 (m, 1H), 2.90-2.83 (m, 1H), 2.11-1.97 (m, 2H). ¹⁹F NMR (376MHz, Methanol-d4) δ −63.29, −72.80 (t, J=8.6 Hz), −77.82.

Example 608.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 537.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 9.15 (s, 1H), 8.40 (d, J=2.0 Hz, 1H), 8.31 (s, 1H), 8.14(s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 5.45-5.32 (m, 2H),3.20-3.13 (m, 1H), 3.07-2.99 (m, 1H), 2.29-2.20 (m, 1H), 2.02-1.93 (m,1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −63.29, −72.85 (t, J=8.6 Hz),−77.90.

Example 609.5-(8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 536.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.42 (s, 1H), 8.36 (d, J=1.9 Hz, 1H), 8.28 (s, 1H), 8.04(d, J=1.9 Hz, 1H), 8.01 (s, 1H), 7.76-7.68 (m, 1H), 7.17-7.08 (m, 1H),4.20 (q, J=10.2 Hz, 2H), 2.86-2.77 (m, 2H), 2.04-1.89 (m, 2H). ¹⁹F NMR(376 MHz, Methanol-d4) δ −61.40, −66.48 (t, J=10.2 Hz), −77.90.

Example 610.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-b]pyridine.ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),8.12 (s, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.67 (s, 1H), 7.43 (d, J=6.7 Hz,1H), 7.33 (d, J=8.2 Hz, 1H), 5.35-5.07 (m, 2H), 3.26-3.20 (m, 1H),3.11-3.04 (m, 1H), 2.20-2.11 (m, 1H), 2.07-1.98 (m, 1H).

Example 611.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine.ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 9.42 (s, 1H),8.74 (s, 1H), 8.24-8.20 (m, 2H), 7.77 (s, 1H), 7.47 (d, J=6.8 Hz, 1H),5.49 (q, J=8.5 Hz, 2H), 3.30-3.25 (m, 1H), 3.15-3.02 (m, 1H), 2.40-2.27(m, 1H), 2.19-2.11 (m, 1H).

Example 612.5-(3-fluoro-8-((1R,2R)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1R,2R)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1R,2R)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine.ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 9.42 (d, J=0.9Hz, 1H), 8.74 (d, J=0.9 Hz, 1H), 8.24-8.19 (m, 2H), 7.77 (s, 1H), 7.47(d, J=6.8 Hz, 1H), 5.49 (q, J=8.5 Hz, 2H), 3.11-3.03 (m, 1H), 2.41-2.27(m, 1H), 2.21-2.09 (m, 1H).

Example 613.5-(3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(5-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 504.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.24 (s, 1H),8.09 (d, J=1.0 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J=5.8 Hz, 1H), 7.53 (d,J=6.6 Hz, 1H), 7.48 (d, J=9.9 Hz, 1H), 5.32-5.21 (m, 2H), 3.07-2.97 (m,1H), 2.91-2.81 (m, 1H), 2.08-1.93 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −73.00 (t, J=8.7 Hz), −78.15, −128.62-−128.72 (m),−157.01 (d, J=6.8 Hz).

Example 614.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(racemic mixture). ES/MS m/z: 469.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.63 (d, J=1.5 Hz, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.35 (s,1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.16 (d, J=2.0 Hz, 1H), 8.13 (s, 1H),5.31 (q, J=8.7 Hz, 2H), 3.07-2.97 (m, 1H), 2.91-2.84 (m, 1H), 2.21-2.13(m, 1H), 2.13-2.06 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.99 (t,J=8.7 Hz), −78.12.

Example 615.5-(8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.90 (d, J=1.6 Hz, 1H), 8.42 (d, J=2.0 Hz, 1H), 8.35 (d,J=2.4 Hz, 1H), 8.32 (s, 1H), 8.21 (s, 1H), 8.10 (d, J=2.2 Hz, 1H), 5.27(q, J=8.5 Hz, 2H), 3.24-3.13 (m, 2H), 2.29-2.17 (m, 1H), 2.07-1.97 (m,1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −73.70-−73.81 (m), −77.98,−155.45-−155.76 (m).

Example 616.5-(8-((1S,2S)-2-(1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole(racemic mixture). ES/MS m/z: 494.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.46-8.39 (m, 1H), 8.36-8.31 (m, 1H), 8.17-8.09 (m, 1H),7.80-7.74 (m, 1H), 7.72-7.66 (m, 1H), 7.55-7.45 (m, 1H), 5.76-5.56 (m,1H), 3.61-3.48 (m, 1H), 3.47-3.35 (m, 1H), 3.33-3.18 (m, 1H), 3.08-2.93(m, 2H), 2.93-2.80 (m, 1H), 2.11-1.95 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −76.50-−76.67 (m), −77.96.

Example 617.5-(8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(1,1,1-trifluoropropan-2-yl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 482.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.41-8.34 (m,1H), 8.32-8.28 (m, 1H), 8.09 (s, 1H), 8.07-8.05 (m, 2H), 7.77-7.72 (m,1H), 7.60 (s, 1H), 7.20-7.10 (m, 1H), 5.61-5.48 (m, 1H), 2.98-2.88 (m,1H), 2.86-2.76 (m, 1H), 2.12-2.02 (m, 1H), 2.02-1.94 (m, 1H), 1.90-1.82(m, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.17 (d, J=7.1 Hz), —77.26(d, J=7.1 Hz), −77.82.

Example 618.5-(3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 504.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H),8.13 (s, 1H), 7.68 (s, 1H), 7.51 (d, J=6.6 Hz, 1H), 7.42 (s, 1H), 6.86(d, J=11.1 Hz, 1H), 5.22 (q, J=8.8 Hz, 2H), 2.97-2.80 (m, 2H), 2.07-1.97(m, 1H), 1.95-1.84 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.92 (t,J=8.7 Hz), −78.17, −121.17 (d, J=11.1 Hz), −156.97 (d, J=6.7 Hz).

Example 619.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(racemic mixture). ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.63 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 8.14(s, 1H), 7.70 (s, 1H), 7.49 (d, J=6.7 Hz, 1H), 5.31 (q, J=8.6 Hz, 2H),3.07-2.98 (m, 1H), 2.97-2.88 (m, 1H), 2.16-2.08 (m, 1H), 2.01-1.93 (m,1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.98-−73.13 (m), −78.18, −157.07(d, J=6.9 Hz).

Example 620.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 536.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.35 (d, J=1.9Hz, 1H), 8.28 (s, 1H), 8.03 (d, J=1.9 Hz, 1H), 8.01 (s, 1H), 7.81 (d,J=8.5 Hz, 1H), 7.72 (s, 1H), 7.40 (dd, J=8.5, 1.4 Hz, 1H), 5.31 (q,J=8.5 Hz, 2H), 3.00-2.91 (m, 1H), 2.87-2.77 (m, 1H), 2.09-1.95 (m, 2H).¹⁹F NMR (376 MHz, Methanol-d4) δ −63.38 (q, J=5.2 Hz), −72.14-−72.27(m), −77.84.

Example 621.5-(3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 505.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.89 (s, 1H), 8.35 (d, J=2.2 Hz, 1H), 8.24 (s, 1H), 7.84(s, 1H), 7.57 (d, J=6.4 Hz, 1H), 5.26 (q, J=8.5 Hz, 2H), 3.30-3.20 (m,1H), 3.20-3.12 (m, 1H), 2.20-2.13 (m, 1H), 2.12-2.05 (m, 1H). ¹⁹F NMR(376 MHz, Methanol-d4) δ −73.68-−73.80 (m), −78.21, −155.36-−155.48 (m),−156.64 (d, J=6.6 Hz).

Example 622.5-(8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(4-(2-(trifluoromethyl)phenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 490.80 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.60 (d, J=5.3 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.28 (s,1H), 8.07 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.88-7.81 (m, 1H), 7.76-7.70(m, 1H), 7.69-7.62 (m, 1H), 7.50 (s, 1H), 7.45-7.40 (m, 1H), 7.34-7.30(m, 1H), 3.15-3.06 (m, 1H), 3.01-2.94 (m, 1H), 2.21-2.13 (m, 1H),2.03-1.96 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −58.41, −77.91.

Example 623.5-(8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4-(2,4-difluorophenyl)pyridin-2-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 459.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.61 (d, J=5.4 Hz, 1H), 8.33 (d, J=1.9 Hz, 1H), 8.27 (s,1H), 8.02 (s, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.75-7.66 (m, 2H), 7.61-7.56(m, 1H), 7.20-7.11 (m, 2H), 3.14-3.06 (m, 1H), 3.04-2.95 (m, 1H),2.23-2.12 (m, 1H), 2.08-2.00 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−77.81, −109.90-−110.16 (m), —114.35-−114.66 (m).

Example 624.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine(racemic mixture). ES/MS m/z: 537.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 9.12 (s, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.30 (s, 1H), 8.09(s, 1H), 8.04 (d, J=1.9 Hz, 1H), 7.89 (s, 1H), 5.34 (q, J=8.5 Hz, 1H),3.19-2.97 (m, 2H), 2.26-2.17 (m, 1H), 2.02-1.94 (m, 1H). ¹⁹F NMR (376MHz, Methanol-d4) δ −63.74-−63.89 (m), —72.24-−72.39 (m), −77.82.

Example 625.5-(8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(trifluoromethyl)imidazo[1,5-a]pyridin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 454.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.36 (d, J=1.9 Hz, 1H), 8.34 (d, J=7.5 Hz, 1H), 8.28 (s,1H), 8.04 (d, J=1.9 Hz, 1H), 8.00 (s, 1H), 7.67 (s, 1H), 7.52 (s, 1H),6.93 (dd, J=7.5, 1.8 Hz, 1H), 2.87-2.73 (m, 2H), 1.99 (t, J=7.5 Hz, 2H).¹⁹F NMR (376 MHz, Methanol-d4) δ −64.76, −77.89.

Example 626.5-(8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(2-(difluoromethyl)-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 518.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.36 (d, J=2.0 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J=2.0 Hz,1H), 8.03 (s, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.35 (dd,J=8.5, 1.6 Hz, 1H), 7.18 (t, J=52.1 Hz, 1H), 5.29 (q, J=8.6 Hz, 2H),2.99-2.89 (m, 1H), 2.85-2.75 (m, 1H), 2.10-1.95 (m, 2H). ¹⁹F NMR (376MHz, Methanol-d4) δ −72.12-−72.31 (m), −77.84, −117.52 (dq, J=52.0, 5.5Hz).

Example 627.5-(8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5-(2,2,2-trifluoroethoxy)quinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5-(2,2,2-trifluoroethoxy)quinoline(racemic mixture). ES/MS m/z: 495.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 9.04 (dd, J=5.0, 1.6 Hz, 1H), 9.02-8.98 (m, 1H), 8.28 (d,J=1.7 Hz, 1H), 8.25 (s, 1H), 7.92 (d, J=1.7 Hz, 1H), 7.91 (s, 1H), 7.80(dd, J=8.5, 5.0 Hz, 1H), 7.66 (s, 1H), 7.26 (s, 1H), 4.94 (q, J=8.3 Hz,2H), 3.10-2.94 (m, 2H), 2.18-2.06 (m, 2H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −75.99 (t, J=8.3 Hz), −77.84.

Example 628.5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine.ES/MS m/z: 487.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.64 (d, J=1.9Hz, 1H), 8.32-8.27 (m, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.71 (s, 1H),7.49 (d, J=6.7 Hz, 1H), 5.31 (q, J=8.7 Hz, 2H), 3.08-2.98 (m, 1H),2.98-2.87 (m, 1H), 2.17-2.09 (m, 1H), 2.04-1.91 (m, 1H). ¹⁹F NMR (376MHz, Methanol-d4) δ −73.03 (t, J=8.7 Hz), −78.18, −157.05 (d, J=6.5 Hz).

Example 629.5-(8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)[1,2,4]triazolo[1,5-b]pyridazine.ES/MS m/z: 487.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H),8.27 (s, 1H), 8.12 (d, J=2.3 Hz, 1H), 8.10 (s, 1H), 7.59 (d, J=8.4 Hz,1H), 7.07 (dd, J=8.4, 5.9 Hz, 1H), 5.21 (q, J=8.5 Hz, 2H), 3.26-3.18 (m,1H), 2.92-2.83 (m, 1H), 2.25-2.16 (m, 1H), 1.98-1.89 (m, 1H). ¹⁹F NMR(376 MHz, Methanol-d4) δ −73.70-−73.83 (m), −78.18, −143.42-−143.63 (m).

Example 630.5-(3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 505.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.88 (s, 1H),8.34 (d, J=2.2 Hz, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.49 (d, J=6.6 Hz,1H), 5.26 (q, J=8.5 Hz, 3H), 3.34-3.21 (m, 1H), 3.22-3.11 (m, 1H),2.19-2.13 (m, 1H), 2.13-2.06 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−73.76 (td, J=8.4, 5.1 Hz), −78.15, −155.66-−155.77 (m), −156.98 (d,J=6.4 Hz).

Example 631.5-(8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith8-((1S,2S)-2-(4,7-difluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 504.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.36 (d, J=1.9 Hz, 1H), 8.28 (s, 1H), 8.21 (d, J=2.1 Hz,1H), 8.06-8.01 (m, 2H), 6.80 (dd, J=10.2, 4.3 Hz, 1H), 5.24 (q, J=8.5Hz, 2H), 3.08-2.96 (m, 1H), 2.90-2.81 (m, 1H), 2.08-1.95 (m, 2H). ¹⁹FNMR (376 MHz, Methanol-d4) δ −73.69 (td, J=8.4, 5.5 Hz), −77.84, −125.10(dd, J=23.9, 10.2 Hz), −147.40-−147.65 (m).

Example 632.5-(8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture) was prepared in a manner described for Example 1, butreplacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-(2,2,2-trifluoroethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine(racemic mixture). ES/MS m/z: 536.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.59 (s, 1H), 8.36 (d, J=1.8 Hz, 1H), 8.29 (s, 1H),8.05-8.01 (m, 2H), 7.72 (d, J=9.5 Hz, 1H), 7.44 (d, J=9.5 Hz, 1H),4.49-4.30 (m, 2H), 2.97-2.91 (m, 1H), 2.91-2.82 (m, 1H), 2.11-2.02 (m,1H), 2.02-1.94 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −64.78, −65.01(t, J=10.1 Hz), −77.91.

Examples 633 and 634.5-(8-((1S,2S)-2-(4-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(4-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1R,2R)-2-(4-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere chirally separated from the Example 39 by SFC AD-H column (35%MeOH).

Example 633:5-(8-((1S,2S)-2-(4-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 380.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53-11.45 (m,2H), 8.25 (s, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.74 (s, 1H), 7.47 (s, 1H),7.39-7.25 (m, 4H), 2.87-2.78 (m, 1H), 2.75-2.65 (m, 1H), 2.14-2.04 (m,1H), 1.77-1.67 (m, 1H).

Example 634:5-(8-((1R,2R)-2-(4-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 380.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58-11.50 (m,2H), 8.37-8.30 (m, 1H), 8.03 (d, J=6.2 Hz, 1H), 7.88 (s, 1H), 7.57 (s,1H), 7.40-7.34 (m, 2H), 7.32-7.25 (m, 2H), 2.85-2.76 (m, 1H), 2.76-2.68(m, 1H), 2.10-2.00 (m, 1H), 1.82-1.70 (m, 1H).

Example 635.5-(8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-fluoro-5-(trifluoromethyl)pyridin-2-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas chirally separated from the racemic mixture Example 582 by SFC AD-Hcolumn (30% EtOH). ES/MS m/z: 433.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.68 (s, 1H), 8.15 (s, 1H), 8.11-8.08 (m, 1H), 7.93-7.83(m, 1H), 7.69-7.66 (m, 1H), 7.64 (s, 1H), 3.27-3.08 (m, 2H), 2.17-2.05(m, 2H).

Example 636.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas chirally separated from the racemic mixture Example 591 by SFC AD-Hcolumn (35% EtOH). ES/MS m/z: 469.10 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 9.05 (s, 1H), 8.32 (s, 1H), 8.16 (s, 1H), 8.11 (d, J=1.4Hz, 1H), 7.69 (d, J=1.4 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 5.25 (q,J=8.7 Hz, 2H), 3.20-3.10 (m, 1H), 3.04-2.95 (m, 1H), 2.15-2.07 (m, 1H),2.05-1.97 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −72.97 (t, J=8.8Hz).

Example 637.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas chirally separated from the racemic mixture Example 608 by SFC AD-Hcolumn (25% EtOH). ES/MS m/z: 537.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 9.10 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.79 (s, 1H),7.69 (s, 1H), 7.64 (s, 1H), 5.37 (q, J=8.6 Hz, 2H), 3.25-3.16 (m, 1H),3.06-2.98 (m, 1H), 2.18-2.09 (m, 1H), 2.05-1.97 (m, 1H). ¹⁹F NMR (376MHz, Methanol-d4) δ −63.30, −72.88 (t, J=8.7 Hz).

Example 638.5-(3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(7-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas chirally separated from the racemic mixture Example 621 by SFC AD-Hcolumn (25% MeOH). ES/MS m/z: 505.20 [M+H]. ¹H NMR (400 MHz,Methanol-d4) δ 8.88 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.22 (s, 1H), 7.77(s, 1H), 7.49 (d, J=6.6 Hz, 1H), 5.26 (q, J=8.5 Hz, 2H), 3.30-3.21 (m,1H), 3.22-3.10 (m, 1H), 2.20-2.13 (m, 1H), 2.13-2.06 (m, 1H). ¹⁹F NMR(376 MHz, Methanol-d4) δ −73.76 (td, J=8.5, 5.2 Hz), −78.15,−155.66-−155.78 (m), −156.98 (d, J=6.4 Hz).

Example 639 and 640.5-(8-((1S,2S)-2-((S)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1S,2S)-2-((R)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-((S)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneand5-(8-((1S,2S)-2-((R)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewere diastereomerically separated (racemic compounds) from the mixtureExample 616 by repeated RP-HPLC purification. The diastereomericstructures were arbitrarily assigned.

5-(8-((1S,2S)-2-((S)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 494.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.33 (d, J=1.8Hz, 1H), 8.27 (s, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.96 (s, 1H), 7.66 (d,J=8.5 Hz, 1H), 7.57 (s, 1H), 7.41-7.33 (m, 1H), 5.56-5.43 (m, 1H),3.00-2.88 (m, 2H), 2.82-2.73 (m, 1H), 2.06-1.89 (m, 2H). ¹⁹F NMR (376MHz, Methanol-d4) δ −76.79 (d, J=6.8 Hz), −77.86.

5-(8-((1S,2S)-2-((R)-1-(trifluoromethyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 494.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.34 (d, J=1.9Hz, 1H), 8.27 (s, 1H), 8.01 (d, J=1.9 Hz, 1H), 7.97 (s, 1H), 7.67 (d,J=8.5 Hz, 1H), 7.58 (s, 1H), 7.39-7.34 (m, 1H), 5.58-5.45 (m, 1H),3.02-2.88 (m, 2H), 2.87-2.76 (m, 1H), 2.03-1.88 (m, 2H). ¹⁹F NMR (376MHz, Methanol-d4) δ −76.81 (d, J=6.9 Hz), −77.87.

Example 641.5-(8-(2-azabicyclo[2.1.1]hexan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 2-azabicyclo[2.1.1]hexane hydrochloride (138 mg,1.66 mmol, 1 equiv), DIPEA (0.63 mL, 3.61 mmol, 2.4 equiv), and MeCN (6mL) was heated to 85° C. After 4 hours, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.1.1]hexane.ES/MS m/z: 235.10 [M+H].

Step 2: A solution of2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.1.1]hexane (379mg, 1.61 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (446mg, 2.42 mol, 1.5 equiv), cesium carbonate (1052 mg, 3.23 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (118 mg, 10 mol %) in 1:2water/1,4-dioxane (8 mL) was heated to 80° C. After 90 minutes, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.1.1]hexane.ES/MS m/z: 339.20 [M+H].

Step 3: A solution of2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.1.1]hexane(112 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80° C. After 14 hours,the reaction mixture was filtered and washed with MeCN. The remainingsolids were dried under vacuum, affording5-(8-(2-azabicyclo[2.1.1]hexan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 311.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.26-8.21 (m,2H), 7.96 (d, J=2.1 Hz, 1H), 7.51 (s, 1H), 3.86 (s, 2H), 3.16-3.10 (m,1H), 2.29-2.17 (m, 2H), 1.64-1.53 (m, 2H).

Example 642.5-(8-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (150 mg,0.65 mmol, 1 equiv), (1R,4S)-2-azabicyclo[2.2.1]heptane hydrochloride(63 mg, 0.65 mmol, 1 equiv), DIPEA (0.27 mL, 1.55 mmol, 2.4 equiv), andMeCN (2.5 mL) was heated to 85° C. After 20 hours, the reaction mixturewas directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording8-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-6-chloroimidazo[1,2-b]pyridazine.ES/MS m/z: 249.10 [M+H].

Step 2: A solution of8-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-6-chloroimidazo[1,2-b]pyridazine(159 mg, 0.64 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(176 mg, 0.96 mol, 1.5 equiv), cesium carbonate (417 mg, 1.28 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (47 mg, 10 mol %) in 1:2water/1,4-dioxane (3 mL) was heated to 80° C. After 18 hours, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording8-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 353.20 [M+H].

Step 3: A solution of8-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(167 mg) in 1:1 1N HCl:MeOH (2.5 mL) was heated to 70° C. After 10hours, the reaction mixture was filtered and purified by RP-HPLC (5-80%MeCN/H₂O with TFA modifier), affording5-(8-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 325.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H),11.35 (d, J=6.1 Hz, 1H), 8.04 (s, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.60 (s,1H), 6.58 (bs, 1H), 3.61 (bs, 1H), 3.19 (bs, 1H), 2.70 (s, 1H),1.83-1.61 (m, 4H), 1.61-1.53 (m, 1H), 1.45-1.33 (m, 1H).

Example 643.5-(8-(2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionein the manner described for Example 642, but replacing(1R,4S)-2-azabicyclo[2.2.1]heptane hydrochloride with racemic2-azabicyclo[2.2.1]heptane hydrochloride. ES/MS m/z: 325.20 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.47 (d, J=6.2 Hz, 1H), 11.42 (s, 1H), 8.17(s, 1H), 7.97 (d, J=6.2 Hz, 1H), 7.78 (s, 1H), 6.78 (s, 1H), 3.73 (bs,1H), 3.27 (bs, 1H), 2.72 (s, 1H), 1.83-1.64 (m, 4H), 1.63-1.55 (m, 1H),1.49-1.35 (m, 1H).

Example 644.5-(8-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 6,6-difluoro-2-azabicyclo[2.2.1]heptanehydrochloride (221 mg, 1.66 mmol, 1.1 equiv), DIPEA (0.63 mL, 3.61 mmol,2.4 equiv), and MeCN (6 mL) was heated to 85° C. After hours, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording6-chloro-8-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 285.10 [M+H].

Step 2: A solution of6-chloro-8-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazine(462 mg, 1.62 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(448 mg, 2.43 mol, 1.5 equiv), cesium carbonate (1057 mg, 3.25 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (119 mg, 10 mol %) in 1:2water/1,4-dioxane (25 mL) was heated to ° C. After 3 hours, the reactionmixture was directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording8-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 389.20 [M+H].

Step 3: A solution of8-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(368 mg) in 1:1 1N HCl:MeOH (4 mL) was heated to 80° C. After 20 hours,the reaction mixture was filtered and purified by RP-HPLC (5-80%MeCN/H₂O with TFA modifier), affording5-(8-(6,6-difluoro-2-azabicyclo[2.2.1]heptan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 361.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),8.16 (s, 1H), 7.86 (s, 1H), 7.33 (s, 1H), 5.30 (s, 1H), 3.98-3.84 (m,1H), 3.53-3.47 (m, 1H), 2.95 (s, 1H), 2.40-2.21 (m, 1H), 2.14-1.89 (m,3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −78.15, −92.03-−93.17 (m),−114.17-−115.45 (m).

Example 645.5-(8-(1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexanehydrochloride (250 mg, 1.66 mmol, 1.1 equiv), DIPEA (0.63 mL, 3.61 mmol,2.4 equiv), and MeCN (6 mL) was heated to 85° C. After 6 hours, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording6-chloro-8-(1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 303.10 [M+H].

Step 2: A solution of6-chloro-8-(1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazine(313 mg, 1.03 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(228 mg, 1.24 mol, 1.2 equiv), cesium carbonate (674 mg, 2.07 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (76 mg, 10 mol %) in 1:2water/1,4-dioxane (5 mL) was heated to 80° C. After 16 hours, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording6-(2,4-dimethoxypyrimidin-5-yl)-8-(1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 407.20 [M+H].

Step 3: A solution of6-(2,4-dimethoxypyrimidin-5-yl)-8-(1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazine(305 mg) in 1:1 1N HCl:MeOH (4 mL) was heated to 80° C. After 20 hours,the reaction mixture was filtered and washed with MeCN. The remainingsolids were dried under vacuum, affording5-(8-(1-(trifluoromethyl)-3-azabicyclo[3.1.0]hexan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 379.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.25-8.22 (m,2H), 7.93 (d, J=2.0 Hz, 1H), 7.34 (s, 1H), 4.38-4.31 (m, 1H), 4.21-4.12(m, 2H), 4.06-3.98 (m, 1H), 2.41-2.32 (m, 1H), 1.60-1.51 (m, 1H),1.07-0.98 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −70.11.

Example 646.5-(8-(7-azabicyclo[2.2.1]heptan-7-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 7-azabicyclo[2.2.1]heptane hydrochloride (161 mg,1.66 mmol, 1.1 equiv), DIPEA (0.63 mL, 3.61 mmol, 2.4 equiv), and MeCN(6 mL) was heated to 85° C. After 5 hours, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording8-(7-azabicyclo[2.2.1]heptan-7-yl)-6-chloroimidazo[1,2-b]pyridazine.ES/MS m/z: 249.10 [M+H].

Step 2: A solution of8-(7-azabicyclo[2.2.1]heptan-7-yl)-6-chloroimidazo[1,2-b]pyridazine (114mg, 0.46 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (102mg, 0.55 mol, 1.2 equiv), cesium carbonate (300 mg, 0.92 mmol, 2 equiv),and PdCl₂(dppf)-CH₂Cl₂ (34 mg, 10 mol %) in 1:2 water/1,4-dioxane (2.4mL) was heated to 80° C. After 1 hour, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording8-(7-azabicyclo[2.2.1]heptan-7-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 353.20 [M+H].

Step 3: A solution of8-(7-azabicyclo[2.2.1]heptan-7-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(118 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80° C. After 20 hours,the reaction mixture was filtered and washed with MeCN. The remainingsolids were dried under vacuum, affording5-(8-(7-azabicyclo[2.2.1]heptan-7-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 325.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.25-8.14 (m,2H), 7.92 (bs, 1H), 7.63 (bs, 1H), 4.77-4.68 (m, 2H), 2.00-1.90 (m, 4H),1.70-1.62 (m, 4H).

Example 647.5-(8-(2-azabicyclo[2.2.2]octan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 2-azabicyclo[2.2.2]octane hydrochloride (184 mg,1.66 mmol, 1.1 equiv), DIPEA (0.63 mL, 3.61 mmol, 2.4 equiv), and MeCN(6 mL) was heated to 85° C. After 5 hours, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.2.2]octane.ES/MS m/z: 263.10 [M+H].

Step 2: A solution of2-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.2.2]octane (426mg, 1.62 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (358mg, 1.95 mol, 1.2 equiv), cesium carbonate (1057 mg, 3.24 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (119 mg, 10 mol %) in 1:2water/1,4-dioxane (8 mL) was heated to 80° C. After 16 hours, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.2.2]octane.ES/MS m/z: 367.20 [M+H].

Step 3: A solution of2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-azabicyclo[2.2.2]octane(365 mg) in 1:1 1N HCl:MeOH (4 mL) was heated to 80° C. After 20 hours,the reaction mixture was filtered and washed with MeCN. The remainingsolids were dried under vacuum, affording5-(8-(2-azabicyclo[2.2.2]octan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 339.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.23 (s, 1H),8.20 (d, J=2.0 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.41 (s, 1H), 4.38 (s,1H), 3.89-3.76 (m, 2H), 2.18-2.07 (m, 3H), 1.99-1.77 (m, 6H).

Example 648.5-(8-(8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 8-azabicyclo[3.2.1]octane hydrochloride (192 mg,1.73 mmol, 1.15 equiv), DIPEA (0.63 mL, 3.61 mmol, 2.4 equiv), and MeCN(6 mL) was heated to 85° C. After 6 hours, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording8-(8-azabicyclo[3.2.1]octan-8-yl)-6-chloroimidazo[1,2-b]pyridazine.ES/MS m/z: 263.10 [M+H].

Step 2: A solution of8-(8-azabicyclo[3.2.1]octan-8-yl)-6-chloroimidazo[1,2-b]pyridazine (313mg, 1.19 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (263mg, 1.43 mol, 1.2 equiv), cesium carbonate (776 mg, 2.38 mmol, 2 equiv),and PdCl₂(dppf)-CH₂Cl₂ (87 mg, 10 mol %) in 1:2 water/1,4-dioxane (8 mL)was heated to 80° C. After 2 hours, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording8-(8-azabicyclo[3.2.1]octan-8-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 367.20 [M+H].

Step 3: A solution of8-(8-azabicyclo[3.2.1]octan-8-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine(310 mg) in 1:1 1N HCl:MeOH (4 mL) was heated to 80° C. After 20 hours,the reaction mixture was filtered and washed with MeCN. The remainingsolids were dried under vacuum, affording5-(8-(8-azabicyclo[3.2.1]octan-8-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 339.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.24 (s, 1H),8.22 (d, J=2.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.58 (s, 1H), 4.76 (bs,2H), 2.22 (dd, J=8.8, 4.6 Hz, 2H), 2.09-1.88 (m, 5H), 1.68-1.57 (m, 3H).

Example 649.1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-methylpyrrolidine-3-carbonitrile

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 3-methylpyrrolidine-3-carbonitrile hydrochloride(182 mg, 1.66 mmol, 1.1 equiv), DIPEA (0.63 mL, 3.61 mmol, 2.4 equiv),and MeCN (6 mL) was heated to 85° C. After 6 hours, the reaction mixturewas directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-methylpyrrolidine-3-carbonitrile.ES/MS m/z: 262.10 [M+H].

Step 2: A solution of1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-methylpyrrolidine-3-carbonitrile(447 mg, 1.71 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(377 mg, 2.05 mol, 1.2 equiv), cesium carbonate (1113 mg, 3.42 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (125 mg, 10 mol %) in 1:2water/1,4-dioxane (5 mL) was heated to 80° C. After 16 hours, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affording1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-methylpyrrolidine-3-carbonitrile.ES/MS m/z: 366.10 [M+H].

Step 3: A solution of1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-methylpyrrolidine-3-carbonitrile(274 mg) in 1:1 1N HCl:MeOH (4 mL) was heated to 80° C. After 20 hours,the reaction mixture was filtered and purified by RP-HPLC (5-80%MeCN/H₂O with TFA modifier), affording1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-methylpyrrolidine-3-carbonitrile.ES/MS m/z: 338.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.19 (s, 1H),8.12 (d, J=1.7 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.08 (s, 1H), 4.47 (d,J=11.0 Hz, 1H), 4.13-4.02 (m, 2H), 3.91 (d, J=11.0 Hz, 1H), 2.66-2.56(m, 1H), 2.35-2.21 (m, 1H), 1.65 (s, 3H).

Example 650.5-(8-(3-azabicyclo[3.1.1]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (350 mg,1.51 mmol, 1 equiv), 3-azabicyclo[3.1.1]heptane hydrochloride (161 mg,1.66 mmol, 1.1 equiv), DIPEA (0.63 mL, 3.61 mmol, 2.4 equiv), and MeCN(6 mL) was heated to 85° C. After 6 hours, the reaction mixture wasdirectly purified by SiO₂ chromatography (0-100% EtOAc/Hex), affording3-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.1]heptane.ES/MS m/z: 249.10 [M+H].

Step 2: A solution of3-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.1]heptane (333mg, 1.34 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid (296mg, 1.61 mol, 1.2 equiv), cesium carbonate (872 mg, 2.68 mmol, 2 equiv),and PdCl₂(dppf)-CH₂Cl₂ (98 mg, 10 mol %) in 1:2 water/1,4-dioxane (8 mL)was heated to 80° C. After 4 hours, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.1]heptane.ES/MS m/z: 353.20 [M+H].

Step 3: A solution of3-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-3-azabicyclo[3.1.1]heptane(246 mg) in 1:1 1N HCl:MeOH (4 mL) was heated to 80° C. After 20 hours,the reaction mixture was filtered and washed with MeCN. The remainingsolids were dried under vacuum, affording5-(8-(3-azabicyclo[3.1.1]heptan-3-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 325.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H),8.25 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.47 (s, 1H), 4.12 (s,4H), 2.77-2.69 (m, 2H), 2.42-2.32 (m, 2H), 1.61-1.52 (m, 2H).

Example 651.5-(8-(2-azabicyclo[3.2.1]octan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (50mg, 0.16 mmol, 1 equiv), 2-azabicyclo[3.2.1]octane hydrochloride (27 mg,0.24 mmol, 1.5 equiv), and DIPEA (0.071 mL, 0.41 mmol, 2.5 equiv) in NMP(2 mL) was microwaved at 120° C. After 90 minutes, the reaction mixturewas directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording5-(8-(2-azabicyclo[3.2.1]octan-2-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 339.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.21 (s, 1H),8.16 (d, J=1.9 Hz, 1H), 7.87 (d, J=1.9 Hz, 1H), 7.51 (s, 1H), 4.79-4.75(m, 1H), 3.79-3.65 (m, 1H), 3.53-3.38 (m, 1H), 2.58-2.44 (m, 1H),2.01-1.58 (m, 8H).

Example 652.5-(8-(3-(chloromethyl)-3-(hydroxymethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (150 mg,0.45 mmol, 1 equiv), 2-oxa-7-azaspiro[3.4]octane (76 mg, 0.67 mmol, 1.5equiv), and DIPEA (0.23 mL, 1.34 mmol, 3 equiv) in MeCN (3.75 mL) washeated to 100° C. After 16 hours, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording6-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-oxa-6-azaspiro[3.4]octane.ES/MS m/z: 377.10 [M+H].

Step 2: A solution of6-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-oxa-6-azaspiro[3.4]octane(58 mg) in 1:1 1N HCl:MeOH (1 mL) was heated to 80° C. After 4 hours,the reaction mixture was filtered and purified by RP-HPLC (10-90%MeCN/H₂O with TFA modifier), affording5-(8-(3-(chloromethyl)-3-(hydroxymethyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 377.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),8.16 (d, J=1.9 Hz, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.17 (s, 1H), 4.04-3.94(m, 2H), 3.84 (s, 2H), 3.81 (s, 2H), 3.69 (s, 2H), 2.22-2.11 (m, 2H).

Example 653.5-(8-(2-oxa-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

A solution of5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (20mg, 0.065 mmol, 1 equiv) and 2-oxa-7-azaspiro[3.4]octane (15 mg, 0.13mmol, 2 equiv) in NMP (1 mL) was heated to 100° C. After 2 hours, thereaction mixture was filtered and purified by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier), affording5-(8-(2-oxa-6-azaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 341.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H),8.11-8.08 (m, 1H), 7.80-7.76 (m, 1H), 7.06 (s, 1H), 4.81-4.67 (m, 4H),4.17 (s, 2H), 3.88 (t, J=7.0 Hz, 2H), 2.43 (t, J=7.0 Hz, 2H). ¹⁹F NMR(376 MHz, Methanol-d4) δ −77.82.

Example 654.2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-N-isopropylacetamide

To a solution of2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)aceticacid (20 mg, 0.056 mmol, 1 equiv), propan-2-amine (0.01 mL, 0.11 mmol, 2equiv), and HATU (32 mg, 0.084 mmol, 1.5 equiv) in DMF (1 mL) was addedDIPEA (0.05 mL, 0.28 mmol, 5 equiv). After 14 hours, the reactionmixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFA modifier),affording2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-N-isopropylacetamide.ES/MS m/z: 398.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),8.14 (d, J=1.8 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.14 (s, 1H), 4.15-4.05(m, 1H), 4.07-3.93 (m, 2H), 3.91-3.79 (m, 1H), 3.64-3.54 (m, 1H),2.86-2.73 (m, 1H), 2.41 (d, J=7.4 Hz, 2H), 2.37-2.26 (m, 1H), 1.94-1.77(m, 1H), 1.18 (d, J=6.6 Hz, 3H), 1.17 (d, J=6.6 Hz, 3H).

Example 655.5-(8-(1-(3,3,3-trifluoropropanoyl)-1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: To a solution of tert-butyl6-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate(690 mg) in 1:1 1N HCl:MeOH (5 mL) was heated to 80° C. After 24 hours,the reaction mixture was concentrated to afford5-(8-(1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.This material was used in the next step without purification. ES/MS m/z:4340.20 [M+H].

Step 2: To a solution of5-(8-(1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(30 mg, 0.088 mmol, 1 equiv), 3,3,3-trifluoropropanoic acid (23 mg, 0.18mmol, 2 equiv), and HATU (50 mg, 0.13 mmol, 1.5 equiv) in DMF (1 mL) wasadded DIPEA (1 drop). After 1 hour, the reaction mixture was purified byRP-HPLC (10-90% MeCN/H₂O with TFA modifier), affording5-(8-(1-(3,3,3-trifluoropropanoyl)-1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 450.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H),8.17 (d, J=2.0 Hz, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.21 (s, 1H), 4.45 (d,J=11.6 Hz, 1H), 4.26-4.14 (m, 3H), 4.07 (d, J=11.6 Hz, 1H), 4.03-3.94(m, 1H), 3.24-3.13 (m, 2H), 2.89-2.82 (m, 1H), 2.63-2.53 (m, 1H),2.51-2.43 (m, 1H), 2.43-2.33 (m, 1H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−64.61 (t, J=10.7 Hz), −77.91.

Example 656.5-(8-(1-acetyl-1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: To a solution of tert-butyl6-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate(690 mg) in 1:1 1N HCl:MeOH (5 mL) was heated to 80° C. After 24 hours,the reaction mixture was concentrated to afford5-(8-(1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.This material was used in the next step without purification. ES/MS m/z:340.20 [M+H].

Step 2: To a solution of5-(8-(1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(30 mg, 0.088 mmol, 1 equiv), acetic anhydride (9 mg, 0.088 mmol, 1equiv) in CH₂Cl₂ (1 mL) was added DMAP (54 mg, 0.44 mmol, 5 equiv).After 1 hour, the reaction mixture was purified by RP-HPLC (10-90%MeCN/H₂O with TFA modifier), affording5-(8-(1-acetyl-1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 382.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.21 (s, 1H),8.14 (d, J=1.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.13 (s, 1H), 4.48 (d,J=11.4 Hz, 1H), 4.26-4.04 (m, 4H), 4.02-3.90 (m, 1H), 2.95-2.80 (m, 1H),2.59-2.50 (m, 1H), 2.49-2.40 (m, 1H), 2.40-2.29 (m, 1H), 1.87 (s, 3H).

Example 657.5-(8-(1-isobutyryl-1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: To a solution of tert-butyl6-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate(690 mg) in 1:1 1N HCl:MeOH (5 mL) was heated to 80° C. After 24 hours,the reaction mixture was concentrated to afford5-(8-(1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.This material was used in the next step without purification. ES/MS m/z:340.20 [M+H].

Step 2: To a solution of5-(8-(1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(30 mg, 0.088 mmol, 1 equiv), isobutyric anhydride (28 mg, mmol, 2equiv) in CH₂Cl₂ (1 mL) was added DMAP (54 mg, 0.44 mmol, 5 equiv).After 1 hour, the reaction mixture was purified by RP-HPLC (10-90%MeCN/H₂O with TFA modifier), affording5-(8-(1-isobutyryl-1,6-diazaspiro[3.4]octan-6-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 410.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H),8.14 (d, J=1.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.15 (s, 1H), 4.43 (d,J=11.4 Hz, 1H), 4.25-4.11 (m, 3H), 4.07 (d, J=11.4 Hz, 1H), 4.01-3.89(m, 1H), 2.88-2.77 (m, 1H), 2.61-2.38 (m, 3H), 2.39-2.30 (m, 1H), 1.07(d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H).

Example 658.2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(1-(trifluoromethyl)cyclopropyl)acetamide

Step 1: To a solution of2-(1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)acetic acid (1000mg, 3.77 mmol, 1 equiv) in CH₂Cl₂ (7.5 mL) was added trifluoroaceticacid (2.5 mL). After 6 hours, the reaction mixture was concentrated toafford 2-(4,4-difluoropyrrolidin-3-yl)acetic acid TFA salt. Thismaterial was used in the next step without purification. ¹H NMR (400MHz, DMSO-d6) δ 3.84-3.60 (m, 3H), 3.18 (t, J=11.0 Hz, 1H), 3.08-2.86(m, 1H), 2.69-2.48 (m, 2H).

Step 2: To a solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (1040mg, 3.09 mmol, 1 equiv) in NMP (10 mL) was added DIPEA (1.29 mL, 7.43mmol, 2.4 equiv) and crude 2-(4,4-difluoropyrrolidin-3-yl)acetic acid(562 mg, 3.40 mmol, 1.1 equiv). The reaction mixture was heated to 115°C. After 48 hours, the reaction mixture was cooled to room temperatureand acidified with 1N HCl (10 mL). The layers were separated, and theaqueous layer was exhaustively extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-40%MeOH/CH₂Cl₂), affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid. ES/MS m/z: 421.20 [M+H].

Step 3: To a solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid (30 mg, 0.071 mmol, 1 equiv),1-(trifluoromethyl)cyclopropan-1-amine hydrochloride (18 mg, 0.14 mmol,2 equiv), and HATU (41 mg, 0.11 mmol, 1.5 equiv) in DMF (1 mL) was addedDIPEA (0.06 mL, 0.36 mmol, 5 equiv). After 1 hour, the reaction mixturewas directly purified by SiO₂ chromatography (0-15% MeOH/CH₂Cl₂),affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(1-(trifluoromethyl)cyclopropyl)acetamide.ES/MS m/z: 428.20 [M+H].

Step 4: A solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(1-(trifluoromethyl)cyclopropyl)acetamide(63 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80° C. After 14 hours,the reaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier), affording2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(1-(trifluoromethyl)cyclopropyl)acetamide.ES/MS m/z: 500.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.13 (s, 1H),8.04 (s, 1H), 7.70 (s, 1H), 6.92 (s, 1H), 4.46-4.28 (m, 3H), 3.78-3.67(m, 1H), 3.26-3.13 (m, 1H), 2.79-2.64 (m, 1H), 2.57-2.40 (m, 1H),1.32-1.26 (m, 2H), 1.16-1.06 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−75.71, −77.96, −110.80-−114.52 (m).

Example 659.2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-isopropylacetamide

Step 1: To a solution of2-(1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)acetic acid (1000mg, 3.77 mmol, 1 equiv) in CH₂Cl₂ (7.5 mL) was added trifluoroaceticacid (2.5 mL). After 6 hours, the reaction mixture was concentrated toafford 2-(4,4-difluoropyrrolidin-3-yl)acetic acid. This material wasused in the next step without purification. ¹H NMR (400 MHz, DMSO-d6) δ3.84-3.60 (m, 3H), 3.18 (t, J=11.0 Hz, 1H), 3.08-2.86 (m, 1H), 2.69-2.48(m, 2H).

Step 2: To a solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (1040mg, 3.09 mmol, 1 equiv) in NMP (10 mL) was added DIPEA (1.29 mL, 7.43mmol, 2.4 equiv) and 2-(4,4-difluoropyrrolidin-3-yl)acetic acid TFA salt(562 mg, 3.40 mmol, 1.1 equiv). The reaction mixture was heated to 115°C. After 48 hours, the reaction mixture was cooled to room temperatureand acidified with 1N HCl (10 mL). The layers were separated, and theaqueous layer was exhaustively extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-40%MeOH/CH₂Cl₂), affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid. ES/MS m/z: 421.20 [M+H].

Step 3: To a solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid (50 mg, 0.12 mmol, 1 equiv), propan-2-amine (0.02 mL, 0.24 mmol, 2equiv), and HATU (68 mg, 0.18 mmol, 1.5 equiv) in DMF (1 mL) was addedDIPEA (0.04 mL, 0.24 mmol, 2 equiv). After 1 hour, the reaction mixturewas directly purified by SiO₂ chromatography (0-15% MeOH/CH₂Cl₂),affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-isopropylacetamide.ES/MS m/z: 462.30 [M+H].

Step 4: A solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-isopropylacetamide(75 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80° C. After 14 hours,the reaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier), affording2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-isopropylacetamide.ES/MS m/z: 434.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.18 (s, 1H),8.12 (m, 1H), 7.82-7.78 (m, 1H), 7.12-7.03 (m, 1H), 4.44-4.28 (m, 3H),4.04-3.93 (m, 1H), 3.82-3.72 (m, 1H), 2.74-2.64 (m, 1H), 2.51-2.37 (m,1H), 1.17 (d, J=6.6 Hz, 3H), 1.16 (d, J=6.6 Hz, 3H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −78.09, −111.05-−114.49 (m).

Example 660.2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide

Step 1: To a solution of2-(1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)acetic acid (1000mg, 3.77 mmol, 1 equiv) in CH₂Cl₂ (7.5 mL) was added trifluoroaceticacid (2.5 mL). After 6 hours, the reaction mixture was concentrated toafford 2-(4,4-difluoropyrrolidin-3-yl)acetic acid. This material wasused in the next step without purification. ¹H NMR (400 MHz, DMSO-d6) δ3.84-3.60 (m, 3H), 3.18 (t, J=11.0 Hz, 1H), 3.08-2.86 (m, 1H), 2.69-2.48(m, 2H).

Step 2: To a solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (1040mg, 3.09 mmol, 1 equiv) in NMP (10 mL) was added DIPEA (1.29 mL, 7.43mmol, 2.4 equiv) and 2-(4,4-difluoropyrrolidin-3-yl)acetic acid TFA salt(562 mg, 3.40 mmol, 1.1 equiv). The reaction mixture was heated to 115°C. After 48 hours, the reaction mixture was cooled to room temperatureand acidified with 1N HCl (10 mL). The layers were separated, and theaqueous layer was exhaustively extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-40%MeOH/CH₂Cl₂), affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid. ES/MS m/z: 421.20 [M+H].

Step 3: To a solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid (30 mg, 0.071 mmol, 1 equiv), 3-fluorobicyclo[1.1.1]pentan-1-aminehydrochloride (14 mg, 0.14 mmol, 2 equiv), and HATU (41 mg, 0.11 mmol,1.5 equiv) in DMF (1 mL) was added DIPEA (0.06 mL, 0.36 mmol, 5 equiv).After 30 minutes, the reaction mixture was directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide.ES/MS m/z: 504.20 [M+H].

Step 4: A solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide(18 mg) in 1:1 1N HCl:MeOH (1 mL) was heated to 80° C. After 14 hours,the reaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier), affording2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)-N-(3-fluorobicyclo[1.1.1]pentan-1-yl)acetamide.ES/MS m/z: 476.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.14 (s, 1H),8.07 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 6.98 (s, 1H), 4.45-4.29(m, 3H), 3.78-3.69 (m, 1H), 3.23-3.13 (m, 1H), 2.77-2.65 (m, 1H),2.51-2.41 (m, 1H), 2.38-2.33 (m, 6H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−78.00, −111.09-−114.51 (m), —169.13-−169.21 (m).

Example 661.N-(bicyclo[1.1.1]pentan-1-yl)-2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)acetamide

Step 1: To a solution of2-(1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-3-yl)acetic acid (1000mg, 3.77 mmol, 1 equiv) in CH₂Cl₂ (7.5 mL) was added trifluoroaceticacid (2.5 mL). After 6 hours, the reaction mixture was concentrated toafford 2-(4,4-difluoropyrrolidin-3-yl)acetic acid. This material wasused in the next step without purification. ¹H NMR (400 MHz, DMSO-d6) δ3.84-3.60 (m, 3H), 3.18 (t, J=11.0 Hz, 1H), 3.08-2.86 (m, 1H), 2.69-2.48(m, 2H).

Step 2: To a solution of8-bromo-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine (1040mg, 3.09 mmol, 1 equiv) in NMP (10 mL) was added DIPEA (1.29 mL, 7.43mmol, 2.4 equiv) and 2-(4,4-difluoropyrrolidin-3-yl)acetic acid TFA salt(562 mg, 3.40 mmol, 1.1 equiv). The reaction mixture was heated to 115°C. After 48 hours, the reaction mixture was cooled to room temperatureand acidified with 1N HCl (10 mL). The layers were separated, and theaqueous layer was exhaustively extracted with EtOAc. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated.Purification was accomplished by SiO₂ chromatography (0-40%MeOH/CH₂Cl₂), affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid. ES/MS m/z: 421.20 [M+H].

Step 3: To a solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)aceticacid (30 mg, 0.071 mmol, 1 equiv), bicyclo[1.1.1]pentan-1-amine (12 mg,0.14 mmol, 2 equiv), and HATU (41 mg, 0.11 mmol, 1.5 equiv) in DMF (1mL) was added DIPEA (0.06 mL, 0.36 mmol, 5 equiv). After 30 minutes, thereaction mixture was directly purified by SiO₂ chromatography (0-100%EtOAc/Hex), affordingN-(bicyclo[1.1.1]pentan-1-yl)-2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)acetamide.ES/MS m/z: 486.20 [M+H].

Step 4: A solution ofN-(bicyclo[1.1.1]pentan-1-yl)-2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)acetamide(38 mg) in 1:1 1N HCl:MeOH (1 mL) was heated to 80° C. After 14 hours,the reaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier), affordingN-(bicyclo[1.1.1]pentan-1-yl)-2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)acetamide.ES/MS m/z: 458.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.15 (s, 1H),8.07 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 6.97 (s, 1H), 4.46-4.30(m, 3H), 3.80-3.70 (m, 1H), 3.24-3.10 (m, 1H), 2.71-2.62 (m, 1H), 2.44(s, 1H), 2.48-2.36 (m, 1H), 2.11 (s, 6H). ¹⁹F NMR (376 MHz, Methanol-d4)δ −77.96, −110.95-−114.72 (m).

Example 662.2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoro-N-isopropylacetamide

Step 1: A solution of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (719 mg,3.09 mmol, 1 equiv), 2,2-difluoro-2-(pyrrolidin-3-yl)acetic acidhydrochloride (511 mg, 3.09 mmol, 1 equiv), DIPEA (1.29 mL, 7.43 mmol,2.4 equiv), and MeCN (20 mL) was heated to 80° C. After 24 hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording2-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoroaceticacid. ES/MS m/z: 317.10 [M+H].

Step 2: To a solution of2-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoroaceticacid (100 mg, 0.32 mmol, 1 equiv), propan-2-amine (0.05 mL, 0.63 mmol, 2equiv), and HATU (180 mg, 0.47 mmol, 1.5 equiv) in DMF (3 mL) was addedDIPEA (0.04 mL, 0.24 mmol, 0.75 equiv). After 1 hour, the reactionmixture was directly purified by SiO₂ chromatography (0-15%MeOH/CH₂Cl₂), affording2-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoro-N-isopropylacetamide.ES/MS m/z: 458.20 [M+H].

Step 3: A solution of2-(1-(6-chloroimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoro-N-isopropylacetamide(271 mg total mass, −30% purity, 0.23 mmol, 1 equiv),(2,4-dimethoxypyrimidin-5-yl)boronic acid (42 mg, 0.23 mol, 1 equiv),cesium carbonate (148 mg, mmol, 2 equiv), and PdCl₂(dppf)-CH₂Cl₂ (17 mg,10 mol %) in 1:2 water/1,4-dioxane (3 mL) was heated to 80° C. After 30minutes, the reaction mixture was directly purified by SiO₂chromatography (0-15% MeOH/CH₂Cl₂), affording2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoro-N-isopropylacetamide.ES/MS m/z: 462.20 [M+H].

Step 4: A solution of2-(1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoro-N-isopropylacetamide(157 mg total mass, −30% purity) in 1:1 1N HCl:MeOH (1 mL) was heated to80° C. After 8 hours, the reaction mixture was filtered and purified byRP-HPLC (10-90% MeCN/H₂O with TFA modifier), affording2-(1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-2,2-difluoro-N-isopropylacetamide.ES/MS m/z: 434.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.18 (s, 1H),8.10 (d, J=1.6 Hz, 1H), 7.77 (d, J=1.6 Hz, 1H), 7.06 (s, 1H), 4.18-3.99(m, 4H), 3.96-3.85 (m, 1H), 2.42-2.19 (m, 2H), 1.23 (d, J=6.6 Hz, 3H),1.20 (d, J=6.6 Hz, 3H). ¹⁹F NMR (376 MHz, Methanol-d4) δ −77.82,−111.64-−116.10 (m).

Example 663.5-(8-(3-((1-isopropyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

A solution of5-(8-(3-(prop-2-yn-1-yl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(50 mg, 0.15 mmol, 1 equiv), 2-azidopropane (11 mg, 0.13 mmol, 0.9equiv), triethylamine (one drop), and CuI (1.4 mg, 5 mol %) in MeCN washeated to ° C. After 16 hours, the reaction mixture was filtered andpurified by RP-HPLC (10-90% MeCN/H₂O with TFA modifier), affording5-(8-(3-((l-isopropyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 422.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H),8.19 (d, J=1.9 Hz, 1H), 7.93 (s, 1H), 7.90 (d, J=1.9 Hz, 1H), 7.20 (s,1H), 4.18-4.02 (m, 1H), 4.03-3.89 (m, 1H), 3.90-3.77 (m, 1H), 3.78-3.64(m, 1H), 3.03-2.88 (m, 2H), 2.87-2.72 (m, 1H), 2.38-2.24 (m, 1H),2.02-1.88 (m, 1H), 1.59 (d, J=6.8 Hz, 3H), 1.59 (d, J=6.8 Hz, 3H).

Example 664.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(1-(trifluoromethyl)cyclopropyl)carbamate

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85° C. After hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80° C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: A solution of(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(130 mg, 0.33 mmol, 1 equiv),1-isocyanato-1-(trifluoromethyl)cyclopropane (248 mg, 1.64 mmol, 5equiv), DIPEA (0.29 mL, 1.64 mmol, 5 equiv), and CH₂Cl₂ (1 mL) washeated to 60° C. After 2 hours, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(1-(trifluoromethyl)cyclopropyl)carbamate. ES/MS m/z: 548.20 [M+H].

Step 4: A solution of(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(1-(trifluoromethyl)cyclopropyl)carbamate (221 mg) in 1:1 1N HCl:MeOH (2mL) was heated to 80° C. After 20 hours, the reaction mixture wasfiltered and washed with 5:1 MeCN/H₂O (20 mL). The remaining solids weredried under vacuum, affording(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(1-(trifluoromethyl)cyclopropyl)carbamate. ES/MS m/z: 520.10 [M+H]. ¹HNMR (400 MHz, Methanol-d4) δ 8.11 (s, 1H), 7.23 (d, J=7.0 Hz, 1H), 6.71(s, 1H), 5.51-5.37 (m, 1H), 4.61-4.44 (m, 1H), 4.40-4.09 (m, 3H),1.32-1.20 (m, 2H), 1.19-1.06 (m, 2H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−76.35, −78.10, −108.98-−110.78 (m), −124.10-−125.53 (m), −157.66 (d,J=7.3 Hz).

Example 665.(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamate

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85° C. After 20 hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80° C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: A solution of(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(100 mg, 0.25 mmol, 1 equiv),1-isocyanato-3-(trifluoromethyl)bicyclo[1.1.1]pentane (197 mg, 1.11mmol, 4.4 equiv), DIPEA (0.22 mL, 1.26 mmol, 5 equiv), and CH₂Cl₂ (2.5mL) was heated to 60° C. After 1 hour, the reaction mixture was directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamate. ES/MS m/z:574.20 [M+H].

Step 4: A solution of(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (163 mg) in 1:11N HCl:MeOH (3 mL) was heated to 80° C. After 20 hours, the reactionmixture was filtered and washed with 5:1 MeCN/H₂O (10 mL). The remainingsolids were dried under vacuum, affording(S)-1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)carbamate. ES/MS m/z:546.20 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 8.11 (s, 1H), 7.24 (d,J=7.1 Hz, 1H), 6.71 (s, 1H), 5.46-5.35 (m, 1H), 4.62-4.43 (m, 1H),4.41-4.02 (m, 3H), 2.24 (s, 6H). ¹⁹F NMR (376 MHz, Methanol-d4) δ−73.59, −78.24, −109.20-−110.65 (m), −123.90-−125.78 (m), −157.61 (d,J=7.1 Hz).

Example 666.(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridazin-3-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85° C. After 20 hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and PdCl₂(dppf)-CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80° C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: To a solution of(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(100 mg, 0.25 mmol, 1 equiv) in DMF (1 mL) was added 60% sodium hydride(19 mg, 0.51 mmol, 2 equiv). After 10 minutes,3-chloro-5-(trifluoromethyl)pyridazine (138 mg, 0.76 mmol, 3 equiv) wasadded, and the reaction mixture was heated to 80° C. After 4 hours, thereaction mixture was cooled to room temperature, quenched with H₂O (2mL), and directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording(S)-8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridazin-3-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 543.20 [M+H].

Step 4: A solution of(S)-8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridazin-3-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(65 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80° C. After 5 hours,the reaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier), affording(S)-5-(8-(3,3-difluoro-4-((5-(trifluoromethyl)pyridazin-3-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 515.10 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ 9.27 (d, J=1.7Hz, 1H), 8.11 (s, 1H), 7.76-7.72 (m, 1H), 7.24 (d, J=7.1 Hz, 1H), 6.75(s, 1H), 6.24-6.15 (m, 1H), 4.72-4.33 (m, 4H). ¹⁹F NMR (376 MHz,Methanol-d4) δ −66.64, −77.87, −109.13-−110.34 (m), −109.15-−124.05 (m),−157.68 (d, J=6.4 Hz).

Example 667.5-(8-(isobutylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(isobutylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-isobutylimidazo[1,2-b]pyridazin-8-amine(20 mg, 0.05 mmol, 1 equiv) in DCM (1 mL) was added TFA solution (0.5mL). The reaction was stirred until complete (0.5 hr), the mixture wasthen concentrated, redissolved in ACN and water, frozen and lyophilizedto give title compound. ES/MS: 301.20 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ11.46 (d, 2H), 8.18 (s, 1H), 8.00 (d, 1H), 7.82 (s, 1H), 7.52 (t, 1H),6.98 (s, 1H), 3.15 (t, 2H), 2.02 (dt, 1H), 0.97 (d, 6H).

Example 668.5-(8-(neopentylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(neopentylamino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 667, but replacing of6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-isobutylimidazo[1,2-b]pyridazin-8-aminewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-neopentylimidazo[1,2-b]pyridazin-8-amine.ES/MS m/z: 315.18 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53-11.44 (m,2H), 8.25 (d, 1H), 8.01 (d, 1H), 7.93 (d, 1H), 7.27 (t, 1H), 7.16 (s,1H), 3.19 (d, 2H), 1.00 (s, 9H).

Example 669.5-(8-((2-methoxyethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2-methoxyethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 667, but replacing of6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-isobutylimidazo[1,2-b]pyridazin-8-aminewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2-methoxyethyl)imidazo[1,2-b]pyridazin-8-amine.ES/MS m/z: 303.13 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.44 (d, 2H), 8.16(d, 1H), 7.98 (d, 1H), 7.76 (s, 1H), 7.37 (s, 1H), 6.95 (s, 1H), 3.61(t, 2H), 3.54-3.46 (m, 2H), 3.31 (s, 3H).

Example 670.5-(8-((2,2-difluoroethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2,2-difluoroethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine(45 mg, 0.08 mmol, 1 equiv) in DCM (1 mL) was added TFA solution (0.5mL). The reaction was stirred until complete (0.5 hr), the mixture wasthen concentrated, redissolved in ACN and water, frozen and lyophilizedto give title compound. ES/MS: 309.09 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ11.46-11.26 (m, 2H), 8.11 (d, 1H), 7.95 (d, 1H), 7.67 (d, 1H), 7.61 (t,1H), 6.24 (tt, 1H), 3.86 (s, 1H), 3.76-3.56 (m, 2H).

Example 671.5-(8-((2,2-difluoroethyl)(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2,2-difluoroethyl)(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a solution of6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-amine(45 mg, 0.08 mmol, 1 equiv) in ACN (1 mL) was added TFA solution (2drops). The reaction vessel was stirred until complete (0.5 hr), themixture was then diluted with water, frozen and lyophilized to givetitle compound. ES/MS: 428.96 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.37(s, 2H), 8.08 (d, 1H), 7.97-7.89 (m, 1H), 7.60 (d, 1H), 7.25 (d, 2H),6.95 (s, 1H), 6.89 (d, 1H), 6.87 (d, 1H), 4.94 (s, 2H), 4.71 (t, 2H),3.72 (s, 3H).

Example 672.5-(8-((2,2,2-trifluoroethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((2,2,2-trifluoroethyl)amino)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 670, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-aminewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(4-methoxybenzyl)-N-(2,2,2-trifluoroethyl)imidazo[1,2-b]pyridazin-8-amine.ES/MS m/z: 327.13 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.41 (dd, 2H),8.15-8.08 (m, 1H), 7.95 (dd, 1H), 7.85 (t, 1H), 7.64 (d, 1H), 4.36-4.31(m, 2H).

Example 673.5-(8-phenethoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-phenethoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as follows: To a microwave vial was added 2-phenylethanol(59 mg, 0.49 mmol) and NMP (2 ml), then sodium hydride 60% dispersion inmineral oil (7.5 mg, 0.19 mmol), allowing to stir for 10 minutes beforeadding5-(8-bromoimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione (30mg, 0.10 mmol). The reaction was then heated to 100° C. for 5 hr. Thereaction was cooled, quenched with water, filtered and purified by HPLCto give the title compound. ES/MS m/z: 350.21 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.55 (d, 2H), 8.28 (d, 1H), 8.05 (d, 1H), 7.78 (s, 1H),7.47-7.37 (m, 3H), 7.33 (dd, 2H), 7.30-7.20 (m, 1H), 4.56 (t, 2H), 3.19(t, 2H).

Example 674.5-(8-(2-phenylpropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-phenylpropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 673, but replacing2-phenylethanol with 2-phenylpropan-1-ol. ES/MS m/z: 364.12 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.60-11.52 (m, 2H), 8.31 (d, 1H), 8.05 (d,1H), 7.83 (s, 1H), 7.48-7.40 (m, 3H), 7.34 (dd, 2H), 7.30-7.21 (m, 1H),4.49 (dd, 1H), 4.40 (dd, 1H), 3.39 (p, 1H), 1.41 (d, 3H).

Example 675.5-(8-(2,2,2-trifluoroethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2,2-trifluoroethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 673, but replacing2-phenylethanol with 2,2,2-trifluoroethanol. ES/MS m/z: 328.15 [M+H]. ¹HNMR (400 MHz, DMSO-d6) δ 11.55 (d, 2H), 8.29 (d, 1H), 8.05 (d, 1H), 7.74(d, 1H), 7.41 (s, 1H), 5.26 (q, 2H).

Example 676.5-(8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 670, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-aminewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 370.16 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d, 2H), 8.31(d, 1H), 8.04 (d, 1H), 7.82 (s, 1H), 7.42 (s, 1H), 4.39 (s, 2H), 1.32(s, 6H).

Example 677.5-(8-(2,2-difluoropropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluoropropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 676, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluoropropoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 324.13 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.54 (m,2H), 8.35 (d, 1H), 8.07 (d, 1H), 7.86 (d, 1H), 7.49 (s, 1H), 4.74 (t,2H), 1.83 (t, 3H).

Example 678.5-(8-isobutoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-isobutoxyimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 676, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-isobutoxyimidazo[1,2-b]pyridazine.ES/MS m/z: 302.14 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65-11.50 (m,2H), 8.34 (d, 1H), 8.07 (d, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 4.13 (d,2H), 2.18 (dq, 1H), 1.06 (d, 6H).

Example 679.5-(8-(neopentyloxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(neopentyloxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 676, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(neopentyloxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 315.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.64 (dd, 1H),11.58 (d, 1H), 8.39 (d, 1H), 8.09 (d, 1H), 7.97 (d, 1H), 7.52 (s, 1H),4.02 (s, 2H), 1.09 (s, 9H).

Example 680.5-(8-((3-methylbutan-2-yl)oxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((3-methylbutan-2-yl)oxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 676, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-((3-methylbutan-2-yl)oxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 316.07 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.60 (dd, 1H),11.56 (d, 1H), 8.36 (d, 1H), 8.07 (d, 1H), 7.92 (d, 1H), 7.50 (s, 1H),4.74 (p, 1H), 2.08-1.98 (m, 1H), 1.35 (d, 3H), 1.01 (dd, 6H).

Example 681.5-(8-(3,3,3-trifluoropropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3,3-trifluoropropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 676, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoro-2,2-dimethylpropoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3,3-trifluoropropoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 342.15 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 2H), 8.25(d, 1H), 8.04 (d, 1H), 7.72 (s, 1H), 7.36 (s, 1H), 4.59 (t, 2H), 2.97(qt, 2H).

Example 682.5-(8-(2,2-difluoro-2-phenylethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluoro-2-phenylethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 673, but replacing2-phenylethanol with 2,2-difluoro-2-phenyl-ethanol. ES/MS m/z: 386.10[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.55 (d, 2H), 8.30 (d, 1H), 8.04 (d,1H), 7.77 (d, 1H), 7.71 (dd, 2H), 7.63-7.51 (m, 3H), 7.46 (s, 1H), 5.09(t, 2H).

Example 683.5-(8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 671, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-N-(2,2-difluoroethyl)-N-(4-methoxybenzyl)imidazo[1,2-b]pyridazin-8-aminewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 337.17 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.42-11.33 (m,2H), 8.07 (d, 1H), 7.95 (d, 1H), 7.62 (d, 1H), 6.64 (s, 1H), 4.39-4.08(m, 1H), 3.97-3.67 (m, 3H), 3.13 (s, 1H), 2.21 (dt, 1H), 2.02 (dt, 1H),1.74 (s, 3H).

Example 684.5-(8-(3-ethynylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-ethynylpyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 683, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynylpyrrolidin-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 323.18 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.38 (dd, 2H),8.05 (d, 1H), 7.94 (d, 1H), 7.59 (d, 1H), 6.61 (s, 1H), 4.30-4.07 (m,1H), 3.95-3.60 (m, 3H), 3.28-3.19 (m, 1H), 3.10 (d, 1H), 2.35-2.22 (m,1H), 2.10-1.97 (m, 1H).

Example 685.5-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 683, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith4-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-methylbut-3-yn-2-ol.ES/MS m/z: 312.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (d, 2H), 8.36(s, 1H), 8.08 (d, 1H), 7.84 (s, 2H), 1.55 (s, 6H).

Example 686.5-(8-(3,3-dimethylbut-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(3,3-dimethylbut-1-yn-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 685, but replacing4-(6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-2-methylbut-3-yn-2-olwith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3,3-dimethylbut-1-yn-1-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 310.19 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, 2H), 8.32(d, 1H), 8.06 (d, 1H), 7.82 (s, 1H), 7.78 (s, 1H), 1.38 (s, 9H).

Example 687.5-(8-(2,2-difluoro-3-hydroxypropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluoro-3-hydroxypropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 683, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropan-1-ol.ES/MS m/z: 340.12 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.63-11.50 (m,2H), 8.34 (d, 1H), 8.07 (d, 1H), 7.90-7.80 (m, 1H), 7.47 (s, 1H), 4.76(t, 2H), 3.85 (t, 2H).

Example 688.5-(8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 683, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(3-ethynyl-3-methylpyrrolidin-1-yl)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 338.14 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.69-11.53 (m,2H), 8.41 (d, 1H), 8.08 (d, 1H), 7.94 (d, 1H), 7.58 (s, 1H), 4.76 (t,2H), 2.14 (tq, 2H), 1.04 (t, 3H).

Example 689.5-(8-(2-cyclopropyl-2,2-difluoroethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2-cyclopropyl-2,2-difluoroethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 688, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith8-(2-cyclopropyl-2,2-difluoroethoxy)-6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 350.12 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.59 (dd, 2H),8.38 (d, 1H), 8.08 (d, 1H), 7.90 (d, 1H), 7.56 (s, 1H), 4.85 (t, 2H),1.63 (s, 1H), 0.77-0.61 (m, 4H).

Example 690.5-(8-(2,2,3,3,3-pentafluoropropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2,3,3,3-pentafluoropropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 688, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2,3,3,3-pentafluoropropoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 378.12 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62-11.52 (m,2H), 8.35 (d, 1H), 8.06 (d, 1H), 7.83 (d, 1H), 7.53 (s, 1H), 5.37 (t,2H).

Example 691.(S)-5-(8-(2-phenylpropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(2-phenylpropoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 688, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith(S)-6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2-phenylpropoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 364.11 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.70-11.63 (m,1H), 11.59 (d, 1H), 8.44 (d, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.64 (s,1H), 7.43 (d, 3H), 7.34 (t, 2H), 7.28-7.22 (m, 1H), 4.52 (dd, 1H), 4.42(dd, 1H), 3.39 (q, 1H), 1.43 (d, 3H).

Example 692.5-(8-(2,2-difluoro-2-(pyridin-2-yl)ethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluoro-2-(pyridin-2-yl)ethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 688, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluoro-2-(pyridin-2-yl)ethoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 387.12 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.65-11.60 (m,1H), 11.58 (d, 1H), 8.73 (dd, 1H), 8.38 (d, 1H), 8.11-8.05 (m, 2H),7.92-7.86 (m, 2H), 7.66-7.60 (m, 2H), 5.25 (t, 2H).

Example 693.5-(8-(2,2-difluoro-2-(1-methyl-1H-imidazol-2-yl)ethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluoro-2-(1-methyl-1H-imidazol-2-yl)ethoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 688, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluoro-2-(1-methyl-1H-imidazol-2-yl)ethoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 390.12 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H),11.55 (s, 1H), 8.31 (d, 1H), 8.07 (d, 1H), 7.78 (d, 1H), 7.51 (s, 1H),7.43 (s, 1H), 7.01 (d, 1H), 5.32 (t, 2H), 3.88 (s, 3H).

Example 694.3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate

3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate was prepared in the manner described for Example 683,but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropylisopropylcarbamate. ES/MS m/z: 425.12 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ11.59 (d, 2H), 8.34 (d, 1H), 8.07 (d, 1H), 7.83 (s, 1H), 7.47 (s, 1H),7.43 (d, 1H), 4.84 (t, 2H), 4.51 (t, 2H), 3.71-3.63 (m, 1H), 1.15 (d,6H).

Example 695.5-(8-(2,2-difluoro-3-(pyridin-2-yloxy)propoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-(2,2-difluoro-3-(pyridin-2-yloxy)propoxy)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 683, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluoro-3-(pyridin-2-yloxy)propoxy)imidazo[1,2-b]pyridazine.ES/MS m/z: 417.06 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.68-11.63 (m,1H), 11.61 (d, 1H), 8.44 (d, 1H), 8.16 (ddd, 1H), 8.09 (d, 1H), 8.01 (d,1H), 7.77 (ddd, 1H), 7.67 (s, 1H), 7.45-7.38 (m, 1H), 7.06 (ddd, 1H),6.99-6.90 (m, 1H), 4.98 (t, 2H), 4.87 (t, 2H).

Example 696.3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,2,2-trifluoroethyl) carbonate

3-((6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,2,2-trifluoroethyl) carbonate was prepared in the manner describedfor Example 683, but replacing6-(2,4-di-tert-butoxypyrimidin-5-yl)-8-(2,2-difluorobutoxy)imidazo[1,2-b]pyridazinewith3-((6-(2,4-di-tert-butoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)oxy)-2,2-difluoropropyl(2,2,2-trifluoroethyl) carbonate. ES/MS m/z: 466.16 [M+H]. ¹H NMR (400MHz, DMSO-d6) δ 11.62-11.54 (m, 2H), 8.35 (d, 1H), 8.06 (d, 1H), 7.84(d, 1H), 7.48 (s, 1H), 4.98-4.86 (m, 4H), 4.80 (t, 2H).

Example 697.5-(3-fluoro-8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoro-8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 504.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62-11.52 (m,2H), 8.04 (d, J=6.2 Hz, 1H), 7.76 (s, 1H), 7.69 (d, J=8.5 Hz, 1H),7.63-7.50 (m, 2H), 7.20 (dd, J=8.5, 1.3 Hz, 1H), 5.31 (q, J=9.0 Hz, 2H),3.04 (ddd, J=9.0, 6.3, 4.4 Hz, 1H), 2.83 (ddd, J=8.9, 6.0, 4.4 Hz, 1H),2.24-2.10 (m, 1H), 1.95-1.85 (m, 1H).

Example 698.5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.ES/MS m/z: 512.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J=7.1 Hz,2H), 8.36 (d, J=1.5 Hz, 1H), 8.21 (d, J=1.8 Hz, 1H), 8.04 (d, J=6.0 Hz,1H), 7.90 (s, 1H), 7.61 (s, 1H), 7.52 (d, J=1.7 Hz, 1H), 4.68 (q, J=9.3Hz, 2H), 2.89 (ddd, J=9.4, 6.3, 4.4 Hz, 1H), 2.84-2.74 (m, 1H), 2.13(dt, J=9.0, 5.4 Hz, 1H), 1.88 (dt, J=8.8, 5.6 Hz, 1H), 1.32 (s, 6H).

Example 699.5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.ES/MS m/z: 512.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.74 (d, J=6.4 Hz,1H), 11.63 (d, J=1.9 Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.24-8.21 (m, 2H),8.11 (d, J=6.3 Hz, 1H), 7.81 (s, 1H), 7.60 (d, J=1.7 Hz, 1H), 4.71 (q,J=9.4 Hz, 2H), 3.05 (dd, J=9.1, 4.9 Hz, 1H), 2.91-2.76 (m, 1H),2.06-1.84 (m, 2H), 1.33 (d, J=1.1 Hz, 6H).

Example 700.5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,3-dimethyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-pyrrolo[3,2-c]pyridin-2-one.ES/MS m/z: 512.20 [M+1-1]. ¹H NMR (400 MHz, Acetonitrile-d3) δ 9.35 (s,1H), 9.25 (s, 1H), 8.44 (s, 1H), 8.19-8.09 (m, 2H), 7.98-7.89 (m, 2H),7.44 (s, 1H), 4.59 (q, J=8.9 Hz, 2H), 3.43-3.33 (m, 1H), 3.19-3.09 (m,1H), 2.21 (dt, J=9.2, 5.9 Hz, 1H), 2.10-1.97 (m, 1H), 1.49 (s, 6H).

Example 701.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 536.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.67 (d, J=6.1 Hz,1H), 11.60 (s, 1H), 8.48 (s, 1H), 8.26 (d, J=1.6 Hz, 1H), 8.07 (dd,J=15.3, 7.2 Hz, 3H), 7.76 (s, 1H), 7.44 (d, J=8.2 Hz, 1H), 5.44-5.18 (m,2H), 3.16-3.06 (m, 2H), 2.12-2.01 (m, 2H).

Example 702.5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one.ES/MS m/z: 529.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.53 (d, J=3.8 Hz,2H), 8.03 (d, J=6.5 Hz, 1H), 7.55 (d, J=7.1 Hz, 1H), 7.47 (s, 1H), 7.31(d, J=7.7 Hz, 1H), 7.13 (s, 1H), 7.00 (dd, J=7.8, 1.4 Hz, 1H), 4.63 (q,J=9.4 Hz, 2H), 2.92-2.82 (m, 1H), 2.76-2.67 (m, 1H), 2.12 (dt, J=9.8,5.3 Hz, 1H), 1.86-1.74 (m, 1H), 1.30 (s, 6H).

Example 703.5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-3,3-dimethyl-1-(2,2,2-trifluoroethyl)indolin-2-one.ES/MS m/z: 511.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.62 (dd, J=24.9,4.1 Hz, 2H), 8.46 (s, 1H), 8.08 (d, J=6.2 Hz, 2H), 7.69 (s, 1H), 7.34(d, J=7.7 Hz, 1H), 7.16 (s, 1H), 7.05-6.98 (m, 1H), 4.65 (q, J=9.4 Hz,2H), 2.91-2.77 (m, 2H), 2.04-1.79 (m, 2H).

Example 704.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 468.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.69 (dd, J=45.4,3.7 Hz, 2H), 8.57 (d, J=1.8 Hz, 1H), 8.22 (s, 1H), 8.12 (d, J=6.2 Hz,1H), 8.00-7.83 (m, 2H), 7.54 (d, J=3.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),6.58 (d, J=3.6 Hz, 1H), 5.22 (ddq, J=53.4, 15.3, 9.2 Hz, 2H), 3.18 (dt,J=9.5, 5.5 Hz, 1H), 3.00 (ddd, J=9.4, 6.1, 4.0 Hz, 1H), 2.09 (d, J=8.0Hz, 1H), 2.02-1.90 (m, 1H).

Example 705.5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 468.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 15.52 (s, 1H),11.82-11.75 (m, 1H), 11.61 (d, J=1.9 Hz, 1H), 9.24 (s, 1H), 8.52 (s,1H), 8.39 (s, 1H), 8.12 (d, J=6.3 Hz, 2H), 7.95 (d, J=3.5 Hz, 1H), 7.86(s, 1H), 7.13 (d, J=3.4 Hz, 1H), 5.54 (q, J=9.1 Hz, 2H), 3.31 (d, J=19.1Hz, 2H), 2.33 (dt, J=9.1, 5.7 Hz, 1H), 2.22 (dt, J=8.8, 5.7 Hz, 1H).

Example 706.5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-(2,4-dimethoxypyrimidin-5-yl)-8-((1S,2S)-2-(3-fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.ES/MS m/z: 486.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.73-11.66 (m,1H), 11.60 (d, J=2.0 Hz, 1H), 9.36 (s, 1H), 8.47 (s, 1H), 8.29 (s, 1H),8.10 (d, J=6.2 Hz, 1H), 8.05-7.98 (m, 2H), 7.80 (s, 1H), 5.41 (q, J=8.9Hz, 2H), 3.15 (s, 2H), 2.35-2.27 (m, 1H), 2.17 (dt, J=8.9, 5.6 Hz, 1H).

Example 707.5-(8-((1S,2S)-2-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1-oxo-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoquinolin-7-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith7-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-2-(2,2,2-trifluoroethyl)isoquinolin-1(2H)-one.ES/MS m/z: 495.20 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.56 (d, J=3.8 Hz,2H), 8.36 (s, 1H), 8.11-8.01 (m, 2H), 7.90 (s, 1H), 7.73-7.59 (m, 3H),7.43 (d, J=7.4 Hz, 1H), 6.72 (d, J=7.4 Hz, 1H), 4.94 (qd, J=9.3, 2.6 Hz,2H), 2.99 (ddd, J=9.4, 6.2, 4.4 Hz, 1H), 2.85 (dt, J=9.8, 5.1 Hz, 1H),2.10 (dt, J=8.9, 5.3 Hz, 1H), 1.88 (dt, J=8.6, 5.4 Hz, 1H).

Example 708.5-(8-((1S,2S)-2-(4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)quinolin-4(1H)-one.ES/MS m/z: 495.10 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 8.41(s, 1H), 8.10-8.03 (m, 1H), 8.08-7.94 (m, 3H), 7.89 (d, J=9.0 Hz, 1H),7.74-7.64 (m, 2H), 6.18 (d, J=7.8 Hz, 1H), 5.35 (q, J=8.8 Hz, 2H),2.99-2.90 (m, 1H), 2.85 (s, 1H), 2.05 (d, J=7.5 Hz, 1H), 1.94-1.85 (m,1H).

Example 709.5-(8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(2,2,2-trifluoroethoxy)quinoline.ES/MS m/z: 495.10 [M+1-1]. ¹H NMR (400 MHz, DMSO-d6) δ 11.70 (d, J=6.3Hz, 1H), 11.60 (d, J=2.0 Hz, 1H), 9.24 (d, J=6.4 Hz, 1H), 8.48 (s, 1H),8.28 (d, J=8.9 Hz, 1H), 8.21 (d, J=1.9 Hz, 1H), 8.09 (dd, J=7.5, 4.3 Hz,2H), 8.00 (dd, J=9.0, 2.0 Hz, 1H), 7.76 (s, 1H), 7.67 (d, J=6.5 Hz, 1H),5.41 (q, J=8.5 Hz, 2H), 3.19 (ddd, J=9.1, 6.2, 4.5 Hz, 1H), 3.11 (s,1H), 2.14 (dt, J=9.0, 5.6 Hz, 1H), 2.00 (dt, J=8.5, 5.6 Hz, 1H).

Example 710.5-(8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-(2,2,2-trifluoroethoxy)isoquinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in a manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4-(2,2,2-trifluoroethoxy)isoquinoline.ES/MS m/z: 495.1 [M+H]. 1 NMR (400 MHz, DMSO-d6) δ 11.68 (d, J=6.4 Hz,1H), 11.61 (d, J=2.0 Hz, 1H), 9.41 (s, 1H), 8.51-8.38 (m, 3H), 8.16-8.05(m, 3H), 7.86-7.75 (m, 2H), 5.18 (q, J=8.7 Hz, 2H), 3.26-3.09 (m, 2H),2.19 (dt, J=9.1, 5.5 Hz, 1H), 2.06 (dt, J=8.6, 5.5 Hz, 1H).

Example 711.(S)-5-(8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas the TFA salt was prepared in the manner described for Example 216,but replacing7-(3,3-difluoro-4,4-dimethylpyrrolidin-1-yl)-5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidinewith(S)-8-(3,3-difluoro-4-((1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 549.0 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.43-11.36 (m, 2H),8.14-8.13 (m, 1H), 8.08 (d, J=1.2 Hz, 1H), 7.94 (d, J=6.1 Hz, 1H), 7.75(d, J=8.8 Hz, 1H), 7.61-7.59 (m, 1H), 7.57 (d, J=1.3 Hz, 1H), 7.00 (dd,J=8.8, 2.1 Hz, 1H), 6.64 (s, 1H), 5.54-5.29 (m, 3H), 4.73-4.09 (m, 4H).

Example 712.(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethyl)benzonitrile

(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethyl)benzonitrilewas prepared as follows: To a solution of(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethyl)benzonitrile(32 mg, 0.059 mmol, 1 equiv) in MeOH (1.0 mL) was added 1 N HCl (1.0mL). The solution was heated to 80° C. and stirred for 3 h and 15 minprior to purification by RP-HPLC (10-90% MeCN/H₂O with TFA, Gemini-NXcolumn) to afford the title compound as the TFA salt. ES/MS m/z: 520.0[M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.44-11.35 (m, 2H), 8.19 (d, J=8.7Hz, 1H), 8.09 (d, J=1.2 Hz, 1H), 7.93 (d, J=6.1 Hz, 1H), 7.73 (d, J=2.6Hz, 1H), 7.65 (dd, J=8.7, 2.6 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 6.64 (s,1H), 5.84-5.76 (m, 1H), 4.70-3.76 (m, 4H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−61.47, −75.30, −106.17-−107.76 (m), −119.74-−121.39 (m).

Example 713.(S)-1-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate

(S)-1-(5-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate was prepared as follows: To a solution of(S)-1-(5-(2,4-dimethoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)-4,4-difluoropyrrolidin-3-ylisopropylcarbamate (26 mg, 0.056 mmol, 1 equiv) in MeOH (2.0 mL) wasadded 1 N HCl (2.0 mL). The solution was heated to 80° C. and stirredfor 2 h prior to purification by RP-HPLC (10-90% MeCN/H₂O with TFA,Gemini-NX column) to afford the title compound as the TFA salt. ES/MSm/z: 436.0 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.85-11.53 (m, 2H), 8.43(d, J=5.9 Hz, 1H), 8.12 (d, J=2.3 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.00(s, 1H), 6.47 (d, J=2.3 Hz, 1H), 5.52-5.39 (m, 1H), 4.70-4.35 (m, 3H),4.22-3.49 (m, 2H), 1.09-1.03 (m, 6H). ¹⁹F NMR (376 MHz, DMSO-d6) δ−75.24, −108.68 (d, J=238.0 Hz), −119.93 (d, J=237.6 Hz).

Example 714.5-(8-((1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 456, but replacing5-bromo-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidinewith6-chloro-8-((1S,2S)-2-(4-methyl-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)imidazo[1,2-b]pyridazine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 482.2 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.53 (d, J=4.1 Hz, 2H), 8.31 (s, 1H), 8.19 (s, 1H), 8.02 (d,J=6.3 Hz, 1H), 7.82 (s, 1H), 7.54 (d, J=11.6 Hz, 2H), 6.89 (s, 1H), 5.37(q, J=9.1 Hz, 2H), 2.95 (ddd, J=9.3, 6.3, 4.4 Hz, 1H), 2.78 (dt, J=9.5,5.4 Hz, 1H), 2.54 (s, 3H), 2.14-2.04 (m, 1H), 1.89 (dt, J=11.0, 5.3 Hz,1H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.06 (t, J=9.2 Hz), −74.98.

Example 715.5-(7-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(7-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 456, but replacing5-bromo-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidinewith6′-((1S,2S)-2-(5-bromopyrazolo[1,5-a]pyrimidin-7-yl)cyclopropyl)-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column), followed by silica gel chromatography (0-100%EtOAc/hexanes). ES/MS m/z: 509.2 [M+H]. ¹H NMR (400 MHz, Methanol-d4) δ8.45 (s, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.18 (s, 1H), 7.09(dd, J=7.8, 1.4 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H),4.61 (q, J=9.0 Hz, 2H), 3.16-3.09 (m, 1H), 2.78-2.69 (m, 1H), 1.95-1.80(m, 2H), 1.75-1.65 (m, 4H).

Example 716.5-(3-fluoro-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

5-(3-fluoro-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 456, but replacing5-bromo-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidinewith5-bromo-3-fluoro-7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidine.Purification was accomplished by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier, Gemini column). ES/MS m/z: 486.1 [M+H]. ¹H NMR (400 MHz,DMSO-d6) δ 11.66 (s, 1H), 11.55 (s, 1H), 8.36 (s, 1H), 8.30 (d, J=3.4Hz, 1H), 8.16 (s, 1H), 7.79-7.67 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 5.41(q, J=8.9 Hz, 2H), 3.10 (q, J=7.0 Hz, 1H), 2.78 (q, J=7.1, 6.6 Hz, 1H),1.95 (t, J=7.5 Hz, 2H). ¹⁹F NMR (376 MHz, DMSO-d6) δ −70.06 (t, J=9.1Hz), −184.76 (d, J=3.5 Hz).

Example 717.5-[8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-[(1S,2S)-2-[6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl]cyclopropyl]-3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridine.ES/MS m/z: 487.1 [M+H]. ¹H NMR (400 MHz, DMSO-d6) δ 11.68 (d, J=6.3 Hz,1H), 11.61 (d, J=2.0 Hz, 1H), 8.66 (d, J=1.7 Hz, 1H), 8.49 (s, 1H), 8.28(d, J=2.0 Hz, 1H), 8.13-8.06 (m, 2H), 7.78 (s, 1H), 5.39 (q, J=9.0 Hz,2H), 3.10-2.98 (m, 2H), 2.18-2.16 (m, 1H), 2.02-2.00 (m, 1H).

Example 718.5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-c]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dionewas chirally separated from the racemic mixture by SFC Cell 2 column(35% EtOH). ES/MS m/z: 512.20 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.55(d, J=6.3 Hz, 2H), 8.63 (s, 1H), 8.31 (d, J=1.2 Hz, 1H), 8.03 (d, J=6.0Hz, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.62 (d, J=6.3 Hz, 2H), 4.73 (q, J=9.2Hz, 2H), 3.26 (d, J=8.9 Hz, 1H), 3.03 (ddd, J=9.0, 6.3, 4.2 Hz, 1H),2.34 (s, 1H), 2.04 (dt, J=9.9, 4.9 Hz, 1H), 1.41 (s, 6H).

Example 719.5-[3-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

Palau' Chlor (8 mg, 0.04 mmoL, 1 equiv) was added to a solution of5-[8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;hydrochloride (20 mg, 0.04 mmol, 1 equiv) in DMF (1 mL). After 1 h, thereaction mixture was directly purified by RP-HPLC (10-80% MeCN/H₂O withTFA modifier), affording5-[3-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 521.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H),11.54 (d, J=2.1 Hz, 1H), 8.67 (d, J=1.7 Hz, 1H), 8.22 (d, J=2.1 Hz, 1H),8.06 (d, J=6.1 Hz, 1H), 7.87 (s, 1H), 7.65 (s, 1H), 5.36 (q, J=8.5 Hz,2H), 3.16 (ddd, J=9.0, 6.2, 4.4 Hz, 1H), 2.90 (ddd, J=9.1, 6.1, 4.4 Hz,1H), 2.27 (dt, J=9.1, 5.4 Hz, 1H), 1.99-1.89 (m, 1H)

Example 720. Preparation of5-[3-fluoro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

SelectFluor (24.5 mg, 0.069 mmoL, 1.3 equiv) was added to a solution of5-[8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;2,2,2-trifluoroacetic acid (32 mg, 0.05 mmol, 1 equiv) in DMF (1 mL).After 16 h, the reaction mixture was directly purified by RP-HPLC(10-80% MeCN/H₂O with TFA modifier), affording5-[3-fluoro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)pyrazolo[4,3-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 505.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.58-11.52 (m,2H), 8.67 (d, J=1.8 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.08-8.01 (m, 1H),7.60-7.53 (m, 2H), 5.36 (q, J=8.9 Hz, 2H), 3.17 (ddd, J=9.0, 6.2, 4.4Hz, 1H), 2.86 (ddd, J=8.9, 6.0, 4.3 Hz, 1H), 2.27 (dt, J=9.1, 5.4 Hz,1H), 1.98-1.88 (m, 1H).

Example 721.5-[3-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

Palau' Chlor (21 mg, 0.1 mmoL, 1 equiv) was added to a solution of5-[8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;hydrochloride (52 mg, 0.1 mmol, 1 equiv) in DMF (1 mL). After 20minutes, the reaction mixture was directly purified by RP-HPLC (15-95%MeCN/H₂O with TFA modifier), affording5-[3-chloro-8-[(1S,2S)-2-[3-fluoro-1-(2,2,2-trifluoroethyl)indazol-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 520.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=5.7 Hz,2H), 8.05 (d, J=6.1 Hz, 1H), 7.86 (s, 1H), 7.77-7.65 (m, 2H), 7.62 (s,1H), 7.20 (dd, J=8.5, 1.3 Hz, 1H), 5.31 (q, J=9.0 Hz, 2H), 3.04 (ddd,J=9.0, 6.3, 4.4 Hz, 1H), 2.84 (ddd, J=8.9, 5.9, 4.4 Hz, 1H), 2.19 (ddd,J=8.9, 6.1, 4.8 Hz, 1H), 1.91 (ddd, J=8.8, 6.3, 4.8 Hz, 1H).

Example 722.5-[3-chloro-8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

Palau' Chlor (8 mg, 0.04 mmoL, 1 equiv) was added to a solution of5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;hydrochloride (20 mg, 0.04 mmol, 1 equiv) in DMF (1 mL). After 20minutes, the reaction mixture was directly purified by RP-HPLC (10-90%MeCN/H₂O with TFA modifier), affording5-[3-chloro-8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)indolin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 545.20 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.54 (d, J=7.2 Hz,2H), 8.05 (d, J=6.0 Hz, 1H), 7.85 (s, 1H), 7.56 (s, 1H), 7.31 (d, J=7.6Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J=7.7, 1.4 Hz, 1H), 4.63 (q, J=9.4 Hz,2H), 2.94-2.67 (m, 2H), 2.16-2.07 (m, 1H), 1.89-1.79 (m, 1H), 1.30 (s,6H).

Example 723. Preparation of5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-6-yl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione

SelectFluor (33 mg, 0.093 mmoL, 1.3 equiv) was added to a solution of5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-6-yl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione;2,2,2-trifluoroacetic acid (45 mg, 0.07 mmol, 1 equiv) in DMF (1 mL).After 16 h, the reaction mixture was directly purified by RP-HPLC(10-80% MeCN/H₂O with TFA modifier), affording5-[8-[(1S,2S)-2-[3,3-dimethyl-2-oxo-1-(2,2,2-trifluoroethyl)pyrrolo[3,2-b]pyridin-6-yl]cyclopropyl]-3-fluoro-imidazo[1,2-b]pyridazin-6-yl]-1H-pyrimidine-2,4-dione.ES/MS m/z: 530.20 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.55 (d, J=3.7 Hz,2H), 8.21 (d, J=1.6 Hz, 1H), 8.04 (d, J=6.4 Hz, 1H), 7.60-7.48 (m, 3H),4.67 (q, J=9.4 Hz, 2H), 2.95 (ddd, J=9.5, 6.2, 4.4 Hz, 1H), 2.76 (dt,J=10.0, 5.4 Hz, 1H), 2.23-2.13 (m, 1H), 1.89-1.74 (m, 1H), 1.31 (s, 6H).

Example 724. Preparation of(S)-5-(8-(4-((6-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85 C. After 20 hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and (dppf)-PdCl₂—CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80 C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: To a cooled (OC) solution(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(50 mg, 0.13 mmol, 1 equiv) in DMF (1 mL) was added 60% sodium hydride(5.8 mg, 0.25 mmol, 2 equiv). After 10 minutes,2-chloro-6-(difluoromethyl)pyridine (62 mg, 0.38 mmol, 3 equiv) wasadded, and the reaction mixture was heated to 80 C. After 1 hour, thereaction mixture was quenched with water at OC and directly purified bySiO₂ chromatography (0-100% EtOAc/Hex), affording(S)-8-(4-((6-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 524.10 [M+H].

Step 4: A solution of(S)-8-(4-((6-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(10 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80 C. After 6 hours, thereaction mixture was directly purified by RP-HPLC (10-90% MeCN/H₂O withTFA modifier), affording(S)-5-(8-(4-((6-(difluoromethyl)pyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 496.10 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.11 (s, 1H),7.90 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.23 (d, J=7.0 Hz, 1H),7.05 (d, J=8.4 Hz, 1H), 6.72 (s, 1H), 6.66 (t, J=55.3 Hz, 1H), 6.04-5.89(m, 1H), 4.69-4.16 (m, 4H). 19F NMR (376 MHz, Methanol-d4) δ −77.74,−109.55-−119.07 (m), —118.63 (dd, J=55.3, 13.9 Hz), −123.69-−124.60 (m),−157.71 (d, J=7.0 Hz).

Example 725. Preparation of(S)-5-(8-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85 C. After 20 hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and (dppf)-PdCl₂—CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80 C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: To a cooled (OC) solution(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(50 mg, 0.13 mmol, 1 equiv) in DMF (1 mL) was added 60% sodium hydride(5.8 mg, 0.25 mmol, 2 equiv). After 10 minutes,4-chloro-2-(difluoromethyl)pyridine (62 mg, 0.38 mmol, 3 equiv) wasadded, and the reaction mixture was heated to 80 C. After 1 hour, thereaction mixture was quenched with water at OC and directly purified bySiO₂ chromatography (0-100% EtOAc/Hex), affording(S)-8-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 524.10 [M+H].

Step 4: A solution of(S)-8-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(60 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80 C. After 20 hours,the reaction mixture was directly purified by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier), affording(S)-5-(8-(4-((2-(difluoromethyl)pyridin-4-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 496.00 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J=5.8Hz, 1H), 8.12 (s, 1H), 7.42 (d, J=2.6 Hz, 1H), 7.31-7.27 (m, 1H), 7.24(d, J=7.1 Hz, 1H), 6.75 (s, 1H), 6.71 (t, J=55.0 Hz, 1H), 5.60-5.49 (m,1H), 4.68-4.27 (m, 4H). 19F NMR (376 MHz, Methanol-d4) δ −78.09,−108.06-−119.07 (m), —118.79 (dd, J=55.0, 2.9 Hz), −123.23-−124.01 (m),−157.63 (d, J=7.1 Hz).

Example 726. Preparation of(S)-5-(8-(3,3-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85 C. After 20 hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and (dppf)-PdCl₂—CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80 C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: To a cooled (OC) solution(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(100 mg, 0.25 mmol, 1 equiv) in DMF (1 mL) was added 60% sodium hydride(12 mg, 0.51 mmol, 2 equiv). After 10 minutes,4-chloro-2-(trifluoromethyl)pyridine (137 mg, 0.76 mmol, 3 equiv) wasadded, and the reaction mixture was heated to 80 C. After 1 hour, thereaction mixture was quenched with water at OC and directly purified bySiO₂ chromatography (0-100% EtOAc/Hex), affording(S)-8-(3,3-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 542.10 [M+H].

Step 4: A solution of(S)-8-(3,3-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(110 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80 C. After 14 hours,the reaction mixture was directly purified by RP-HPLC (10-90% MeCN/H₂Owith TFA modifier), affording(S)-5-(8-(3,3-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 514.10 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.60 (d, J=5.8Hz, 1H), 8.12 (s, 1H), 7.54 (d, J=2.5 Hz, 1H), 7.38 (dd, J=5.8, 2.5 Hz,1H), 7.24 (d, J=7.1 Hz, 1H), 6.75 (s, 1H), 5.64-5.52 (m, 1H), 4.68-4.28(m, 4H). 19F NMR (376 MHz, Methanol-d4) δ −70.19, −107.91-−108.98 (m),−123.16-−124.07 (m), −157.65 (d, J=7.0 Hz).

Example 727. Preparation of(S)-5-(8-(3,3-difluoro-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85 C. After hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and (dppf)-PdCl₂—CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80 C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: To a cooled (OC) solution(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(50 mg, 0.13 mmol, 1 equiv) in DMF (1 mL) was added 60% sodium hydride(5.8 mg, 0.25 mmol, 2 equiv). After 10 minutes,4-chloro-6-(trifluoromethyl)pyrimidine (69 mg, 0.38 mmol, 3 equiv) wasadded, and the reaction mixture was heated to 80 C. After 1 hour, thereaction mixture was quenched with water at OC and directly purified bySiO₂ chromatography (0-100% EtOAc/Hex), affording(S)-8-(3,3-difluoro-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-ES/MSm/z: 543.00 [M+H].

Step 4: To a solution of(S)-8-(3,3-difluoro-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(55 mg) in MeCN (1 mL) was added iodotrimethylsilane (0.14 mL). After 1hour, the reaction mixture was quenched with water at OC and directlypurified by RP-HPLC (10-90% MeCN/H₂O with TFA modifier), affording(S)-5-(8-(3,3-difluoro-4-((6-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 515.10 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.99 (s, 1H),8.12 (s, 1H), 7.46 (d, J=0.9 Hz, 1H), 7.24 (d, J=7.1 Hz, 1H), 6.75 (s,1H), 6.16-6.05 (m, 1H), 4.71-4.26 (m, 4H). 19F NMR (376 MHz,Methanol-d4) δ −72.23, −78.22, −108.88-−109.95 (m), −122.74-−124.16 (m),−157.61 (d, J=7.0 Hz).

Example 728. Preparation of(S)-5-(8-(3,3-difluoro-4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: A solution of 8-bromo-6-chloro-3-fluoroimidazo[1,2-b]pyridazine(2238 mg, 8.94 mmol, 1.1 equiv), (S)-4,4-difluoropyrrolidin-3-olhydrochloride (1000 mg, 8.12 mmol, 1 equiv), DIPEA (3.40 mL, 19.5 mmol,2.4 equiv), and MeCN (20 mL) was heated to 85 C. After 20 hours, thereaction mixture was concentrated and directly purified by SiO₂chromatography (0-100% EtOAc/Hex), affording(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 293.10 [M+H].

Step 2: A solution of(S)-1-(6-chloro-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(2330 mg, 7.96 mmol, 1 equiv), (2,4-dimethoxypyrimidin-5-yl)boronic acid(1611 mg, 8.76 mol, 1.1 equiv), cesium carbonate (5188 mg, 15.9 mmol, 2equiv), and (dppf)-PdCl₂—CH₂Cl₂ (291 mg, 5 mol %) in 1:4water/1,4-dioxane (40 mL) was heated to 80 C. After 24 hours, thereaction mixture was cooled to room temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (3×200 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification was accomplished by SiO₂ chromatography(0-100% EtOAc/Hex), affording(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol.ES/MS m/z: 397.20 [M+H].

Step 3: To a cooled (OC) solution(S)-1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-ol(50 mg, 0.13 mmol, 1 equiv) in DMF (1 mL) was added 60% sodium hydride(5.8 mg, 0.25 mmol, 2 equiv). After 10 minutes,4-chloro-2-(trifluoromethyl)pyrimidine (69 mg, 0.38 mmol, 3 equiv) wasadded, and the reaction mixture was heated to 80 C. After 1 hour, thereaction mixture was quenched with water at OC and directly purified bySiO₂ chromatography (0-100% EtOAc/Hex), affording(S)-8-(3,3-difluoro-4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 543.10 [M+H].

Step 4: A solution of(S)-8-(3,3-difluoro-4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine(55 mg) in 1:1 1N HCl:MeOH (2 mL) was heated to 80 C. After 6 hours, thereaction mixture was directly purified by RP-HPLC (10-90% MeCN/H₂O withTFA modifier), affording(S)-5-(8-(3,3-difluoro-4-((2-(trifluoromethyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 515.10 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J=5.8Hz, 1H), 8.12 (s, 1H), 7.25 (d, J=7.0 Hz, 1H), 7.24 (d, J=5.8 Hz, 1H),6.75 (s, 1H), 6.12-6.03 (m, 1H), 4.70-4.54 (m, 1H), 4.54-4.30 (m, 3H).19F NMR (376 MHz, Methanol-d4) δ −72.90, −78.25, −108.98-−110.32 (m),−122.69-−124.37 (m), −157.62 (d, J=7.0 Hz).

Example 729. Preparation of5-(7-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (1000 mg,6.51 mmol, 1 equiv) and (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid(1746 mg, 6.51 mmol, 1 equiv) in 4:1 1,4-dioxane:H₂O (30 mL) was addedcesium carbonate (5304 mg, 16.3 mmol, 2.5 equiv) and (dppf)-PdCl₂—CH₂Cl₂(238 mg, 5 mol %). The reaction mixture was heated to 80 C. After 2hours, the reaction mixture was filtered, concentrated and directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine. ¹H NMR(400 MHz, DMSO-d₆) δ 9.10 (d, J=7.4 Hz, 1H), 8.79 (s, 1H), 8.22 (d,J=2.3 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 1.66 (s,9H), 1.61 (s, 9H).

Step 2: To a cooled (−78 C) solution of5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine (200 mg,0.59 mmol, 1 equiv) in THF (1.5 mL) was added a 1M THF/Toluene solutionof TMPMgCl·LiCl (0.70 mL, 0.70 mmol, 1.2 equiv). After 15 minutes at −78C, a solution of 1,2-dibromotetrachloroethane (286 mg, 0.88 mmol, 1.5equiv) in THF (1 mL) was added dropwise. The reaction mixture wasgradually allowed to warm to room temperature over two hours. At t=5hours, the reaction mixture was quenched with saturated aqueous NH₄Cland directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording7-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine.¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.90(s, 1H), 6.93 (d, J=2.4 Hz, 1H), 1.67 (s, 9H), 1.61 (s, 9H).

Step 3: A degassed solution of7-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine(30 mg, 0.071 mmol, 1 equiv),4-fluoro-6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-indazole(55 mg, 0.14 mmol, 2 equiv), potassium phosphate tribasic (30 mg, 0.14mmol, 2 equiv), and cataCXium A Pd G3 (10 mg, 20 mol %) in 3:11,4-dioxane:H₂O (1 mL) was heated to 90 C. After 3 hours, the reactionmixture was directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording5-(2,4-di-tert-butoxypyrimidin-5-yl)-7-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidine.ES/MS m/z: 486.10 [M+H], product mass minus tert-butyl groups.

Step 4: To a cooled (OC) solution of5-(2,4-di-tert-butoxypyrimidin-5-yl)-7-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidinein 1:1 H₂O/MeCN (2 mL) was added 10 drops of TFA. After 30 minutes, thereaction mixture was purified by RP-HPLC (10-90% MeCN/H₂O with TFAmodifier), affording5-(7-((1S,2S)-2-(4-fluoro-1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione.ES/MS m/z: 486.10 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H),8.16-8.12 (m, 1H), 7.70 (s, 1H), 7.48 (s, 1H), 6.94 (d, J=11.0 Hz, 1H),6.64 (d, J=2.4 Hz, 1H), 5.22 (q, J=8.8 Hz, 2H), 3.22-3.15 (m, 1H),2.89-2.77 (m, 1H), 2.02-1.87 (m, 2H). 19F NMR (376 MHz, Methanol-d4) δ−72.92 (t, J=8.7 Hz), −78.00, −121.19 (d, J=11.0 Hz).

Example 730. Preparation of5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

Step 1: To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (1000 mg,6.51 mmol, 1 equiv) and (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid(1746 mg, 6.51 mmol, 1 equiv) in 4:1 1,4-dioxane:H₂O (30 mL) was addedcesium carbonate (5304 mg, 16.3 mmol, 2.5 equiv) and (dppf)-PdCl₂—CH₂Cl₂(238 mg, 5 mol %). The reaction mixture was heated to 80 C. After 2hours, the reaction mixture was filtered, concentrated and directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine. ¹H NMR(400 MHz, DMSO-d6) δ 9.10 (d, J=7.4 Hz, 1H), 8.79 (s, 1H), 8.22 (d,J=2.3 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 1.66 (s,9H), 1.61 (s, 9H).

Step 2: To a cooled (−78 C) solution of5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine (200 mg,0.59 mmol, 1 equiv) in THF (1.5 mL) was added a 1M THF/Toluene solutionof TMPMgCl·LiCl (0.70 mL, 0.70 mmol, 1.2 equiv). After 15 minutes at −78C, a solution of 1,2-dibromotetrachloroethane (286 mg, 0.88 mmol, 1.5equiv) in THF (1 mL) was added dropwise. The reaction mixture wasgradually allowed to warm to room temperature over two hours. At t=5hours, the reaction mixture was quenched with saturated aqueous NH₄Cland directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording7-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine.¹H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.90(s, 1H), 6.93 (d, J=2.4 Hz, 1H), 1.67 (s, 9H), 1.61 (s, 9H).

Step 3: A degassed solution of7-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine(30 mg, 0.071 mmol, 1 equiv), racemic6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(52 mg, 0.14 mmol, 2 equiv), potassium phosphate tribasic (30 mg, 0.14mmol, 2 equiv), and cataCXium A Pd G3 (10 mg, 20 mol %) in 3:11,4-dioxane:H₂O (1 mL) was heated to 100 C. After 3 hours, the reactionmixture was directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording6-((1S,2S)-2-(5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture). ES/MS m/z: 469.10 [M+H], product mass minustert-butyl groups.

Step 4: To a cooled (OC) solution of6-((1S,2S)-2-(5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridine(racemic mixture) in 1:1 H₂O/MeCN (2 mL) was added 10 drops of TFA.After 30 minutes, the reaction mixture was purified by RP-HPLC (10-90%MeCN/H₂O with TFA modifier), affording5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture). ES/MS m/z: 469.00 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 9.36 (s, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 8.16 (d, J=2.4Hz, 1H), 8.15 (s, 1H), 7.84 (s, 1H), 6.67 (d, J=2.4 Hz, 1H), 5.43 (q,J=8.6 Hz, 2H), 3.10-3.02 (m, 1H), 2.25-2.11 (m, 2H). 19F NMR (376 MHz,Methanol-d4) δ −72.78 (t, J=8.6 Hz), −77.85.

Example 731. Preparation of5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

Step 1: To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (1000 mg,6.51 mmol, 1 equiv) and (2,4-di-tert-butoxypyrimidin-5-yl)boronic acid(1746 mg, 6.51 mmol, 1 equiv) in 4:1 1,4-dioxane:H₂O (30 mL) was addedcesium carbonate (5304 mg, 16.3 mmol, 2.5 equiv) and (dppf)-PdCl₂—CH₂Cl₂(238 mg, 5 mol %). The reaction mixture was heated to 80 C. After 2hours, the reaction mixture was filtered, concentrated and directlypurified by SiO₂ chromatography (0-100% EtOAc/Hex), affording5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine. ¹H NMR(400 MHz, DMSO-d6) δ 9.10 (d, J=7.4 Hz, 1H), 8.79 (s, 1H), 8.22 (d,J=2.3 Hz, 1H), 7.46 (d, J=7.4 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 1.66 (s,9H), 1.61 (s, 9H).

Step 2: To a cooled (−78 C) solution of5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine (200 mg,0.59 mmol, 1 equiv) in THF (1.5 mL) was added a 1M THF/Toluene solutionof TMPMgCl·LiCl (0.70 mL, 0.70 mmol, 1.2 equiv). After 15 minutes at −78C, a solution of 1,2-dibromotetrachloroethane (286 mg, 0.88 mmol, 1.5equiv) in THF (1 mL) was added dropwise. The reaction mixture wasgradually allowed to warm to room temperature over two hours. At t=5hours, the reaction mixture was quenched with saturated aqueous NH₄Cland directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording7-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine.¹H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.90(s, 1H), 6.93 (d, J=2.4 Hz, 1H), 1.67 (s, 9H), 1.61 (s, 9H).

Step 3: A degassed solution of7-bromo-5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidine(50 mg, 0.12 mmol, 1 equiv), racemic6-((1S,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(87 mg, 0.24 mmol, 2 equiv), potassium phosphate tribasic (51 mg, 0.24mmol, 2 equiv), and cataCXium A Pd G3 (9 mg, 10 mol %) in 3:11,4-dioxane:H₂O (2 mL) was heated to 100 C. After 8 hours, the reactionmixture was directly purified by SiO₂ chromatography (0-100% EtOAc/Hex),affording6-((1S,2S)-2-(5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(racemic mixture). ES/MS m/z: 469.10 [M+H], product mass minustert-butyl groups.

Step 4: To a cooled (OC) solution of6-((1S,2S)-2-(5-(2,4-di-tert-butoxypyrimidin-5-yl)pyrazolo[1,5-a]pyrimidin-7-yl)cyclopropyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridine(racemic mixture) in 1:1 H₂O/MeCN (2 mL) was added 10 drops of TFA.After 30 minutes, the reaction mixture was purified by RP-HPLC (10-90%MeCN/H₂O with TFA modifier), affording5-(7-((1S,2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)cyclopropyl)pyrazolo[1,5-a]pyrimidin-5-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture). ES/MS m/z: 469.10 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.72-8.67 (m, 1H), 8.46 (s, 1H), 8.29 (s, 1H), 8.19-8.17(m, 1H), 8.15 (d, J=2.4 Hz, 1H), 7.76 (s, 1H), 6.65 (d, J=2.4 Hz, 1H),5.30 (q, J=8.7 Hz, 2H), 3.25-3.16 (m, 1H), 2.96-2.85 (m, 1H), 2.11-2.02(m, 1H), 2.00-1.94 (m, 1H). 19F NMR (376 MHz, Methanol-d4) δ −73.03 (t,J=8.7 Hz), −77.99.

Example 732.5-(8-((1S,2S)-2-(8-(2,2,2-trifluoroethoxy)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(8-(2,2,2-trifluoroethoxy)quinolin-6-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-8-(2,2,2-trifluoroethoxy)quinoline.ES/MS m/z: 495.20 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.96 (dd,J=4.9, 1.4 Hz, 1H), 8.80-8.74 (m, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.25 (s,1H), 7.92-7.84 (m, 3H), 7.74 (s, 1H), 7.53 (s, 1H), (q, J=8.4 Hz, 2H),3.02-2.93 (m, 2H), 2.08 (t, J=7.5 Hz, 2H). 19F NMR (376 MHz,Methanol-d4) δ −75.48 (t, J=8.5 Hz), −77.85.

Example 733.5-(8-((1S,2S)-2-(1′-(2,2-difluoropropyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1′-(2,2-difluoropropyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 505.20 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.35 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J=1.9 Hz,1H), 7.98 (s, 1H), 7.07 (s, 1H), 7.03-6.91 (m, 2H), 4.30-4.14 (m, 2H),2.84-2.69 (m, 2H), 1.98-1.86 (m, 2H), 1.72-1.60 (m, 7H). 19F NMR (376MHz, Methanol-d4) δ −77.82, −94.82-−95.15 (m).

Example 734.5-(8-((1S,2S)-2-(1′-((1-fluorocyclopropyl)methyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1′-((1-fluorocyclopropyl)methyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-((1-fluorocyclopropyl)methyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 499.20 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.35 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J=1.9 Hz,1H), 7.98 (s, 1H), 7.11 (s, 1H), 7.01-6.91 (m, 2H), 4.21 (d, J=21.0 Hz,2H), 2.84-2.67 (m, 2H), 1.98-1.86 (m, 2H), 1.70-1.59 (m, 4H), 1.13-0.99(m, 2H), 0.96-0.85 (m, 2H). 19F NMR (376 MHz, Methanol-d4) δ −77.81,−184.03-−184.30 (m).

Example 735.5-(3-fluoro-8-((1S,2S)-2-(1′-((1-fluorocyclopropyl)methyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

To a solution of racemic5-(8-((1S,2S)-2-(1′-((1-fluorocyclopropyl)methyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(13 mg, 0.026 mmol, 1 equiv) in DMF (0.6 mL) was added Selectfluor (19mg, 0.052 mmol, 2 equiv). After 18 hours, the reaction mixture wasdirectly purified by RP-HPLC (10-90% MeCN/H₂O with TFA modifier),affording5-(3-fluoro-8-((1S,2S)-2-(1′-((1-fluorocyclopropyl)methyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemic mixture). ES/MS m/z: 517.20 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.19 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=6.8 Hz, 1H), 7.08(s, 1H), 7.00-6.87 (m, 2H), 4.33-4.13 (m, 2H), 2.85-2.74 (m, 2H),1.97-1.88 (m, 1H), 1.83-1.73 (m, 1H), 1.70-1.56 (m, 4H), 1.11-0.99 (m,2H), 0.95-0.85 (m, 2H). 19F NMR (376 MHz, Methanol-d4) δ −77.82, −157.36(d, J=6.8 Hz), −184.17-−184.52 (m).

Example 736.5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3-tetrafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 541.20 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.34 (d, J=1.9 Hz, 1H), 8.27 (s, 1H), 8.01 (d, J=1.9 Hz,1H), 7.96 (s, 1H), 7.06 (s, 1H), 7.04-6.94 (m, 2H), 6.24 (tt, J=52.6,4.4 Hz, 1H), 4.57-4.37 (m, 2H), 2.84-2.69 (m, 2H), 1.97-1.87 (m, 2H),1.75-1.61 (m, 4H). 19F NMR (376 MHz, Methanol-d4) δ −77.80,−121.57-−121.82 (m), −139.57 (d, J=52.5 Hz).

Example 737.5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(2,2,3,3,3-pentafluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 559.20 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.33 (d, J=1.8 Hz, 1H), 8.26 (s, 1H), 8.00 (d, J=1.8 Hz,1H), 7.94 (s, 1H), 7.09-7.06 (m, 1H), 7.05-6.95 (m, 2H), 4.69-4.57 (m,2H), 2.88-2.67 (m, 2H), 1.96-1.89 (m, 2H), 1.73-1.64 (m, 4H). 19F NMR(376 MHz, Methanol-d4) δ −77.80, −86.44, −120.52-−120.71 (m).

Example 738.5-(8-((1S,2S)-2-(1′-(2-cyclopropyl-2,2-difluoroethyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(Racemic Mixture)

5-(8-((1S,2S)-2-(1′-(2-cyclopropyl-2,2-difluoroethyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith1′-(2-cyclopropyl-2,2-difluoroethyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemic mixture). ES/MS m/z: 531.20 [M+H]. 1H NMR (400 MHz,Methanol-d4) δ 8.36-8.31 (m, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.95 (s,1H), 7.09-7.05 (m, 1H), 7.01-6.93 (m, 2H), 4.39-4.25 (m, 2H), 2.82-2.71(m, 2H), 1.94-1.87 (m, 2H), 1.73-1.55 (m, 5H), 0.90-0.86 (m, 4H). 19FNMR (376 MHz, Methanol-d4) δ −77.80, −106.91-−107.21 (m).

Example 739.5-(8-((1S,2S)-2-(1′-(2,2-difluoropropyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(1′-(2,2-difluoropropyl)-2′-oxospiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith1′-(2,2-difluoropropyl)-6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)cyclopropyl)spiro[cyclopropane-1,3′-indolin]-2′-one.ES/MS m/z: 523.20 [M+H]. 1H NMR (400 MHz, Methanol-d4) δ 8.21 (s, 1H),7.66 (s, 1H), 7.52 (d, J=6.6 Hz, 1H), 7.05 (s, 1H), 7.01-6.85 (m, 2H),4.32-4.14 (m, 2H), 2.83-2.72 (m, 2H), 1.97-1.89 (m, 1H), 1.86-1.78 (m,1H), 1.72-1.59 (m, 7H). 19F NMR (376 MHz, Methanol-d4) δ −78.16,−94.84-−95.17 (m), —156.91 (d, J=6.7 Hz).

Example 740.5-(3-chloro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Palau' Chlor (20 mg, 0.1 mmol) was added to solution of5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(single enantiomer, 49 mg, 0.1 mmol) in DMF (1 ml) at RT. The reactionmixture was stirred at RT for 2 h and then purified with Prep HPLC toafford5-(3-chloro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas single enantiomer. ES/MS m/z: 543.10 [M+H]. 1H NMR (400 MHz,Acetonitrile-d3) δ 9.23 (s, 2H), 8.11 (d, J=6.4 Hz, 1H), 7.77 (s, 1H),7.72 (s, 1H), 7.09-6.82 (m, 3H), 4.51 (q, J=9.3 Hz, 2H), 2.78 (s, 2H),2.05-2.01 (m, 1H), 1.83 (d, J=7.4 Hz, 1H), 1.65 (dt, J=5.1, 3.5 Hz, 4H).19F NMR (377 MHz, Acetonitrile-d3) δ −71.19 (t, J=9.2 Hz), −77.32.

Example 741.5-(2,3-dichloro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Palau' Chlor (20 mg, 0.1 mmol) was added to solution of5-(8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(single enantiomer, 49 mg, 0.1 mmol) in DMF (1 ml) at RT. The reactionmixture was stirred at RT for 2 h and then purified with Prep HPLC toafford5-(2,3-dichloro-8-((1S,2S)-2-(2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dioneas single enantiomer. ES/MS m/z: 577.10 [M+H]. 1H NMR (400 MHz, DMSO-d6)δ 11.57 (d, J=4.3 Hz, 2H), 8.05 (d, J=6.4 Hz, 1H), 7.65 (s, 1H), 7.19(s, 1H), 7.03-6.91 (m, 2H), 4.69 (td, J=9.3, 3.4 Hz, 2H), 2.75 (ddt,J=36.8, 10.0, 4.8 Hz, 2H), 2.13-1.97 (m, 1H), 1.83 (dt, J=8.4, Hz, 1H),1.68-1.47 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ −69.25 (t, J=9.4 Hz),—74.01.

Example 742.(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile

(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 554.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.54-11.12 (m,2H), 8.07 (d, J=8.8 Hz, 1H), 7.97 (d, J=6.0 Hz, 1H), 7.48 (dd, J=2.5,1.4 Hz, 1H), 7.45-7.38 (m, 2H), 6.65 (s, 1H), 5.83-5.56 (m, 1H), 4.49(d, J=64.0 Hz, 4H). 19F NMR (376 MHz, DMSO-d6) δ −57.67, −75.32, −106.91(d, J=241.3 Hz), −120.56 (d, J=239.7 Hz), −155.33 (d, J=7.1 Hz).

Example 743.(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile

(S)-4-((1-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrilewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(S)-4-((1-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)-4,4-difluoropyrrolidin-3-yl)oxy)-2-(trifluoromethoxy)benzonitrile.ES/MS m/z: 536.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.52-11.31 (m,2H), 8.09 (d, J=1.1 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.94 (d, J=6.1 Hz,1H), 7.59 (d, J=1.1 Hz, 1H), 7.48 (dd, J=2.5, 1.3 Hz, 1H), 7.42 (dd,J=8.8, 2.4 Hz, 1H), 6.65 (s, 1H), 5.73 (dt, J=8.0, 4.1 Hz, 1H),4.50-4.18 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ −57.67, −75.37, −106.84(d, J=239.4 Hz), −120.31 (d, J=238.7 Hz).

Example 744.(S)-5-(8-(4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-3-fluoroimidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(S)-8-(4-((4-(difluoromethyl)-5-fluoropyridin-2-yl)oxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)-3-fluoroimidazo[1,2-b]pyridazine.ES/MS m/z: 514.10 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 11.55-11.22 (m,2H), 8.45 (d, J=1.5 Hz, 1H), 7.98 (d, J=6.1 Hz, 1H), 7.43 (d, J=7.1 Hz,1H), 7.39-7.08 (m, 2H), 6.65 (s, 1H), 5.91 (d, J=7.5 Hz, 1H), 4.51 (d,J=43.7 Hz, 3H), 4.19 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ −74.95,−107.75-−108.38 (m), −117.95 (ddd, J=53.4, 11.7, 6.2 Hz), —119.93 (d,J=238.6 Hz), −143.15 (q, J=5.7, 5.2 Hz), −155.37 (d, J=7.4 Hz).

Example 745.(S)-5-(8-(4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-(8-(4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared in the manner described for Example 1, but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith(S)-8-(4-(3-(difluoromethyl)-4-fluorophenoxy)-3,3-difluoropyrrolidin-1-yl)-6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazine.ES/MS m/z: 495.20 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ 9.23 (s,2H), 8.06 (d, J=6.3 Hz, 1H), 7.98 (d, J=1.6 Hz, 1H), 7.74 (d, J=1.6 Hz,1H), 7.30 (d, J=5.7 Hz, 1H), 7.26-7.21 (m, 2H), 7.15-6.79 (m, 2H), 5.23(tt, J=7.7, 3.1 Hz, 1H), 4.55-4.32 (m, 3H), 4.32-4.12 (m, 1H). 19F NMR(377 MHz, Acetonitrile-d3) δ −77.23, −106.24-−109.63 (m), −115.75 (dt,J=54.4, 4.0 Hz), −122.73 (d, J=241.3 Hz), −129.16 (dt, J=11.3, 3.9 Hz).

Example 746.5-(8-((1S,2S)-2-(2′-oxo-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione(racemate)

5-(8-((1S,2S)-2-(2′-oxo-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-1′-(3,3,3-trifluoropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 523.20 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ9.53 (s, 1H), 9.41 (s, 1H), 8.24-8.15 (m, 2H), 8.06 (s, 1H), 7.99 (d,J=2.1 Hz, 1H), 6.98-6.87 (m, 3H), 4.05 (td, J=7.0, 2.8 Hz, 2H), 2.82(dt, J=9.1, 5.2 Hz, 1H), 2.64 (qt, J=11.0, 6.7 Hz, 3H), 1.97-1.90 (m,1H), 1.85 (dt, J=9.1, 5.7 Hz, 1H), 1.58 (dd, J=5.1, 3.6 Hz, 4H). 19F NMR(377 MHz, Acetonitrile-d3) δ −66.52 (t, J=11.1 Hz), −77.19.

Example 747.5-(8-((1S,2S)-2-(7′-fluoro-2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(7′-fluoro-2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-7′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 527.10 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ9.47 (s, 1H), 9.37 (s, 1H), 8.22 (d, J=2.1 Hz, 1H), 8.17 (d, J=6.2 Hz,1H), 8.11 (s, 1H), 8.01 (d, J=2.2 Hz, 1H), 6.93 (t, J=7.1 Hz, 1H), 6.80(d, J=7.9 Hz, 1H), 4.64 (q, J=8.9 Hz, 2H), 2.89-2.67 (m, 2H), 1.95-1.89(m, 1H), 1.88-1.82 (m, 1H), 1.75-1.65 (m, 4H). 19F NMR (376 MHz,Acetonitrile-d3) δ −72.12 (q, J=9.1 Hz), −77.22, −143.08 (qd, J=10.1,6.4 Hz).

Example 748.5-(8-((1S,2S)-2-(5′-fluoro-2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(5′-fluoro-2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-5′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 527.20 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ9.32 (s, 1H), 9.26 (s, 1H), 8.15 (d, J=1.9 Hz, 1H), 8.11 (d, J=6.5 Hz,1H), 7.95 (s, 1H), 7.92 (d, J=1.9 Hz, 1H), 6.96 (d, J=5.9 Hz, 1H), 6.81(d, J=9.7 Hz, 1H), 4.55 (qd, J=9.2, 3.1 Hz, 2H), 2.85 (t, J=6.9 Hz, 2H),1.75-1.53 (m, 4H). 19F NMR (376 MHz, Acetonitrile-d3) δ −71.21 (t, J=9.2Hz), −77.04, −127.92 (dd, J=9.7, 5.8 Hz).

Example 749.5-(8-((1S,2S)-2-(4′-fluoro-2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

5-(8-((1S,2S)-2-(4′-fluoro-2′-oxo-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-6′-yl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dionewas prepared as a racemic mixture in the manner described for Example 1,but replacing8-cyclopropyl-6-(2,4-dimethoxypyrimidin-5-yl)-2-methyl-imidazo[1,2-b]pyridazinewith6′-((1S,2S)-2-(6-(2,4-dimethoxypyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)-4′-fluoro-1′-(2,2,2-trifluoroethyl)spiro[cyclopropane-1,3′-indolin]-2′-one(racemate). ES/MS m/z: 527.20 [M+H]. 1H NMR (400 MHz, Acetonitrile-d3) δ9.37 (s, 1H), 9.31 (s, 1H), 8.20 (d, J=1.9 Hz, 1H), 8.16 (d, J=6.5 Hz,1H), 8.03 (s, 1H), 7.98 (d, J=2.1 Hz, 1H), 6.94 (s, 1H), 6.75 (d, J=11.1Hz, 1H), 4.52 (q, J=9.2 Hz, 2H), 2.69-2.59 (m, 1H), 1.93-1.82 (m, 4H),1.64 (q, J=4.0 Hz, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ −71.19 (t,J=9.2 Hz), −77.24 (d, J=3.8 Hz), −128.71 (d, J=11.3 Hz).

CD73 inhibitor compounds made as described herein are summarized inTable 2.

Lengthy table referenced here US20240043427A1-20240208-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20240043427A1-20240208-T00002 Pleaserefer to the end of the specification for access instructions.

C. PROPHETIC EXAMPLES

The following additional examples may be made using analogous methods.For instance, and further to the disclosure above, synthesis of(2-phenylcyclopropyl)boronic acid derivates has been reported in theliterature, see e.g., Montesinos-Magraner, Marc; et al. AngewandteChemie Int. Ed. (2019), 58, 5930-5935; Zhong, Chongmin; et al. Journalof the American Chemical Society (2010), 132(33), 11440-11442; Shi,Xiaonan; et al. Angewandte Chemie, International Edition (2019), 58(45),16167-16171; and Fawcett, Alexander; et al. Science (Washington, DC,United States) (2017), 357(6348), 283-286.

Example 37.5-(8-(2-(2-chlorophenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Example 40.5-(8-(2-(2-(trifluoromethyl)phenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Example 43.5-(8-(2-(2-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Example 44.5-(8-(2-(3-cyclopropylphenyl)cyclopropyl)imidazo[1,2-b]pyridazin-6-yl)pyrimidine-2,4(1H,3H)-dione

Example 46.5-[8-[2-[2-(trifluoromethoxy)phenyl]cyclopropyl]imidazo[1,2-b]pyridazin-6-yl]-1-{H}-pyrimidine-2,4-dione

Example 51.4-(2-(6-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)imidazo[1,2-b]pyridazin-8-yl)cyclopropyl)benzonitrile

D. BIOCHEMICAL AND BIOLOGICAL ASSAYS CD73 Biochemical IC50 Assay

Compound serial dilutions were pre-spotted into Thermo Nunc assay plate.50 μL CD73 enzyme buffer (CD73 purchased from R&D system=0.6 nM, 25 mMTris, pH 7.4, 5 mM MgCl₂) was added into the assay plate and incubatedfor 15 mins. 50 μL AMP buffer (AMP=30 uM in 25 mM Tris, pH 7.4, 5 mMMgCl₂, final AMP=15 uM, 2×Km, final CD73=0.3 nM) was added into assayplate. After incubation for 60 mins, the supernatant 20 uL wastransferred into 384-well NUNC plate pre-filled with 60 ul Quench buffer(80% organic and 20% water+0.1% FA) with internal standard. The platewas spun down at 4500 rpm for 20 mins, then 200 of supernatant wastransferred to another Nunc plate prefilled with 800 of water. Thesamples were run using Rapid fire.

MDA-MB-231 Cell Based CD73 Activity Assay

MDA-MB-231-GFP cells were seeded in 384-well plates (Greiner 781946) ata density of 10000 cells per well in 50 μL of RPMI medium with 10% HP(human plasma). Cells were plated into assay plate with compoundspre-spotted, for an overnight compound treatment. 50 μL of 400 μM AMP(final concentration 200 μM) using a Bio-tek dispenser. Plates wereincubated for 100 mins. 20 uL supernatant was transferred into 384-wellNUNC plates pre-filled with 600 Quench buffer (80% organic and 20%water+0.1% FA) with internal standard. The plates were spun down at 4500rpm for 20 mins, then 20 μl of supernatant was transferred to anotherNunc plate prefilled with 80 μl of water. The samples were run usingRapid fire.

Results of biochemical and biological assays described above areincluded in Table 4 below.

TABLE 4 Activity Data from CD73 Biochemical IC50 assay and MDA- MB-231Cell based CD73 activity assay Example No. IC50-CD73 (nM) EC50 (nM) 1506.91 412.80 2 32.36 53.28 3 235.34 195.19 4 195.46/230.84190.85/285.49 5 1550.50/2500   2017.80/2534.1  6 163.76 183.85 713.63/13.00  2.08/1.876 8 29.00/45.78 36.14/47.21 9 105.60 29.15 10980.35 472.65 11 109.79 74.11 12 478.83/653.27 507.83/688.82 13368.31/607.33 692.26/896.44 14 301.21 79.15 15 2351.10 920.43 16 362.09332.76 17 >2500.00 3674.10 18 >2500.00 20414.00 19 >2500.00 >25000.0020 >2500.00 >25000.00 21 >2500.00 >25000.00 22 55.78/64.87 46.29/45.1423 >2500.00 >25000.00 24 1255.50 1225.90 25 657.12/556.90 361.47/428.6926 161.19 184.12 27 90.39 145.13 28 16.83 3.59 29 16.32 7.08 30 2.362.56 31 5.49 3.84 32 18.61 6.84 33 9.38 2.04 34 18.19 11.28 36 24.166.51 38 14.34 7.29 41 61.61 18.64 42 28.72 7.59 45 32.63 6.59 47 47.1713.70 48 52.55 16.72 49 17.48 18.99 50 10.69 2.45 52 20.11 2.69 53 20.755.16 54 17.67 3.40 55 >2500.00 872.31 56 >2500.00 4459.70 57 >2500.003304.40 58 547.72 703.80 59 64.99 71.66 60 12.57 6.43 61 12.13 16.64 6227.25 25.12 63 70.48 34.69 64 14.70 2.87 65 13.16 6.71 66 >2500.004466.30 67 30.05 14.27 68 69.48 67.54 69 55.40 47.83 70 221.26 240.15 711491.20 648.56 72 26.46 12.42 73 39.69 17.44 74 169.83 539.77 75 125.72136.01 76 26.45 2.48 77 22.58 13.36 78 1916.80 1227.30 79 25.20 11.65 8543.29 6.08 86 151.62 21.75 87 15.69 3.24 88 9.16 2.93 89 211.40 247.9290 9.91 1.79 91 104.09 62.23 92 15.62 23.57 93 521.90 556.17 94 131.7275.99 95 49.48 39.09 96 773.04 66.64 97 >2500.00 2053.60 98 16.44 7.2399 19.26 6.05 100 98.36 27.48 101 15.87 3.25 102 473.03 258.09 103 70.7645.13 104 195.84 23.16 105 284.54 38.52 106 105.06 93.50 107 46.82 55.02108 34.98 23.78 109 44.47 13.03 110 31.41 7.50 111 205.08 71.48 11220.54 2.23 113 146.89 210.35 114 31.09 5.38 115 13.26 4.21 116 >2500.00717.54CD73 Biochemical IC50 Assay (1 mM NaH₂PO₄)

Compound serial dilutions were pre-spotted into Thermo Nunc assay plate.50 uL CD73 enzyme buffer (CD73 purchased from R&D system=0.6 nM, 25 mMTris, pH 7.4, 5 mM MgCl₂, 1 mM NaH₂PO₄) was added into the assay plateand incubate for 15 mins. 50 uL AMP buffer (AMP=30 uM in 25 mM Tris, pH7.4, 5 mM MgCl₂, final AMP=15 uM, 2×Km, final CD73=0.3 nM) was addedinto assay plate. After incubation for 60 mins, the supernatant (20 uL)was transferred into 384-well NUNC plate pre-filled with 60 uL Quenchbuffer (80% organic and 20% water+0.1% FA) with internal standard. Theplate was spun down at 4500 rpm for 20 mins, then 20 uL of supernatantwas transferred to another Nunc plate prefilled with 80 uL of water. Thesamples were analyzed using Rapid fire.

MDA-MB-231 Cell Based CD73 Activity Assay (DMEM)

MDA-MB-231-GFP cells were seeded in 384-well plates (Greiner 781946) ata density of 3000 cells per well in 50 μL of DMEM medium with 10% HP(human plasma). Cells were plated into assay plate with compoundspre-spotted, for an overnight compound treatment. 50 uL of 400 uM AMP(final concentration will be 200 uM) was added using Bio-tek dispenser.Plates were incubated for 100 mins. 20 uL of supernatant was transferredinto 384-well NUNC plate pre-filled with 60 ul Quench buffer (80%organic and 20% water+0.1% FA) with internal standard. The plates werespun down at 4500 rpm for 20 mins, then 20 ul of supernatant wastransferred to another Nunc plate prefilled with 80 ul of water. Thesamples were analyzed using Rapid fire.

Results of biochemical and biological assays described above areincluded in Table 5 below.

TABLE 5 Activity Data from CD73 Biochemical IC50 assay (1 mM NaH₂PO₄)and MDA-MB-231 Cell based CD73 activity assay (DMEM) Example No.IC50-CD73 (nM) EC50 (nM) 7 0.94 4.15 9 19.43 58.80 22 35.55 104.01 302.08 5.11 31 0.93 4.83 33 0.93 4.71 42 2.08 NA 48 2.73 NA 50 1.37 5.8452 1.14 NA 53 1.52 NA 54 1.98 NA 62 8.47 32.25 63 29.09 47.41 64 1.507.67 67 4.83 30.32 70 134.43 285.22 72 6.97 25.88 73 9.87 31.67 77 3.5028.43 79 4.58 20.85 80 1.81 6.79 81 1.93 8.22 82 3.49 16.38 83 1.47 6.6584 1.10 6.56 85 1.34 17.74 86 5.66 16.61 92 6.57 NA 93 >250.00 684.62 982.00 17.74 109 2.97 NA 110 2.96 28.73 115 1.77 12.89 117 0.89 0.14 1180.79 0.10 119 0.56 1.09 120 0.85 0.85 121 1.08 19.72 122 2.39 11.13 1230.69 0.37 124 2.60 0.62 125 0.71 0.17 126 1.13 0.46 127 1.13 0.17 1281.84 0.40 129 1.11 0.30 130 1.01 0.13 131 0.78 6.10 132 1.21 19.38 1330.92 1.60 134 1.17 22.75 135 1.99 43.96 136 3.11 6.37 137 1.28 4.68 1380.95 0.64 139 4.55 295.79 140 1.68 5.25 141 2.10 24.82 142 0.96 3.76 1435.69 13.05 144 2.30 6.17 145 20.50 41.74 146 6.12 46.69 147 39.00 96.12148 8.00 17.88 149 3.34 7.61 150 1.93 4.79 151 1.36 1.94 152 3.45 17.55153 2.30 8.85 154 1.56 5.75 155 2.04 5.42 156 0.95 1.87 157 1.06 2.81158 0.55 2.52 159 1.76 2.62 160 15.39 27.80 161 4.48 11.02 162 1.64 4.41163 2.13 10.57 164 3.58 13.98 165 5.06 38.72 166 43.04 378.50 167 33.00152.18 168 72.53 305.54 169 73.87 188.57 170 35.41 135.53 171 3.17 14.08172 13.88 65.08 173 3.59 88.18 174 68.95 214.08 175 3.60 23.10 176 10.9959.48 177 7.27 33.25 178 2.65 4.35 179 16.74 60.50 180 2.20 4.67 1812.42 6.42 182 1.24 10.36 183 2.52 23.86 184 2.86 9.45 185 13.46 57.43186 7.57 22.31 187 2.76 12.60 188 17.48 62.54 189 18.09 49.05 190 3.0512.80 191 21.77 45.84 192 6.41 20.88 193 150.68 682.12 194 3.32 468.57195 62.86 217.89 196 98.60 243.13 197 10.98 30.22 198 85.25 191.45199 >250 754.69 200 >250 809.15 201 1.11 6.39 202 1.04 4.25 203 3.0310.32 204 1.63 9.31 205 4.42 16.01 206 4.97 28.69 207 6.05 20.33 2085.88 25.42 209 2.80 24.22 210 4.59 24.35 211 2.33 10.85 212 1.24 0.72213 0.92 0.45 215 1.41 12.10 216 8.01 31.65 217 111.27 583.80 218 3.29455.16 219 8.26 62.59 220 5.34 114.02 221 13.09 74.90 222 17.40 133.18223 31.42 66.38 224 11.95 32.59 225 15.18 105.99 226 121.18 409.61227 >250 487.38 228 31.22 145.75 229 56.93 174.53 230 39.46 64.73 2311.62 2.00 232 2.15 6.18 233 1.17 0.80 234 0.62 6.56 235 0.96 0.82 2361.02 3.04 237 0.70 1.10 238 0.36 5.18 239 0.86 1.17 240 0.28 3.79 2412.13 1.41 242 0.22 2.43 243 22.17 56.11 244 108.16 573.58 245 169.85746.74 246 167.68 212.88 247 41.90 93.60 248 15.07 36.33 249 46.14249.04 250 109.51 686.84 251 17.64 124.63 252 174.47 1242.20 253 20.03159.65 254 26.55 136.31 255 17.49 112.96 256 43.11 184.62 257 51.69102.77 258 52.44 105.81 259 14.73 80.70 260 >250 962.74 261 13.94 139.48262 73.41 564.98 263 10.72 31.42 264 5.59 88.01 265 3.22 77.90 266 1.9313.46 267 34.73 66.59 268 97.03 134.76 269 3.62 27.04 270 1.13 13.67 27133.58 101.75 272 9.90 72.62 273 9.39 58.13 274 16.47 39.44 275 8.6436.24 276 0.91 2.78 277 3.77 78.98 278 3.69 38.94 279 1.07 6.64 280 5.9777.80 281 1.54 8.23 282 1.81 11.65 283 0.87 2.75 284 1.07 3.49 285 1.422.99 286 1.19 2.42 287 3.90 12.46 288 6.86 35.72 289 2.27 7.24 290 3.469.64 291 3.25 18.62 292 2.08 5.72 293 4.75 8.80 294 1.02 1.32 295 1.921.97 296 2.14 4.38 297 1.51 1.31 298 3.78 2.81 299 7.85 24.51 300 1.801.34 301 4.45 19.24 302 3.08 6.99 303 7.74 27.69 304 3.59 3.04 305 4.8121.23 306 1.67 1.41 307 16.05 96.12 308 5.47 6.47 309 42.27 207.60 3100.63 3.40 311 4.72 11.57 312 1.29 4.17 313 2.35 9.78 314 >250 NA 3156.64 27.63 316 0.65 1.21 317 1.01 2.00 318 0.43 0.06 319 0.34 0.07320 >250 1145.70 321 1.12 11.19 322 0.80 0.07 323 0.51 0.06 324 1.151.59 325 1.70 11.23 326 0.91 2.66 327 1.79 50.00 328 3.68 40.55 329 0.640.71 330 1.07 0.51 331 16.16 11.06 332 8.61 26.95 333 0.89 1.91 33424.35 117.98 335 2.80 6.77 336 34.91 >250 337 3.29 15.92 338 10.92 72.82339 0.91 2.60 340 1.48 18.98 341 0.43 0.53 342 1.40 3.82 343 48.17128.66 344 38.35 97.05 345 10.25 97.98 346 6.08 24.40 347 4.39 11.90 34853.99 121.43 349 147.76 124.50 350 12.03 99.31 351 10.64 56.39 352 >2501002.00 353 69.61 109.49 354 90.76 401.47 355 7.56 14.46 356 >250 915.68357 >250 402.47 358 27.79 82.20 359 1.74 22.01 360 0.92 7.56 36 2.722.53 362 2.98 1.00 363 2.00 5.50 364 7.17 34.04 365 7.62 32.82 366 6.6016.39 367 17.50 67.63 368 3.73 20.25 369 21.47 27.51 370 4.02 15.68 3714.95 17.93 372 3.40 9.23 373 2.56 9.61 374 4.10 13.78 375 2.83 11.17 3768.07 19.31 377 7.66 22.65 378 6.45 18.87 379 1.98 5.89 380 3.43 14.26381 0.69 0.16 382 1.63 0.13 383 1.83 49.26 384 1.27 0.24 385 0.68 0.25386 0.92 0.28 387 1.27 0.36 388 0.41 0.21 391 1.01 0.10 392 1.25 0.34393 0.74 0.16 394 5.94 >250 395 2.10 29.93 396 2.00 0.24 397 15.26 22.48398 17.10 29.49 399 12.21 26.98 400 206.94 547.23 401 12.61 52.97 40253.19 135.50 403 8.94 28.48 404 22.93 77.63 405 8.30 21.64 406 25.6598.16 407 1.90 14.71 408 2.35 7.44 409 10.66 37.85 410 816.70 928.30 4116.11 42.56 412 6.00 38.34 413 3.01 34.61 414 2.84 43.84 415 0.79 3.93416 0.71 33.46 417 0.87 12.60 418 0.96 4.71 419 1.23 8.90 420 4.87 13.74421 31.02 65.09 422 72.73 155.14 423 39.24 76.38 424 1.64 4.10 425 1.635.63 426 0.23 4.50 427 0.48 7.40 428 1.38 14.72 429 2.22 8.89 430 0.180.71 431 0.15 0.13 432 0.15 2.58 433 9.71 44.56 434 2.78 14.41 435 6.0066.05 436 0.13 0.43 437 12.76 43.56 438 0.14 0.10 439 0.77 2.63 44038.17 139.79 441 46.30 239.06 442 6.46 19.55 443 156.91 188.03 444 70.98356.17 445 147.60 256.15 446 90.98 1097.10 447 >250 718.46 448 193.671361.40 449 131.52 473.02 450 229.94 249.52 451 67.61 167.23 452 95.3594.77 453 76.04 112.29 454 28.74 50.56 455 14.88 45.96 456 0.53 0.15 4573.52 9.67 458 4.04 13.16 459 0.75 0.38 460 0.46 0.38 461 2.56 11.55 4629.39 NA 463 61.90 NA 464 1.47 16.22 465 0.86 3.24 466 3.47 19.96 4670.85 3.86 468 1.67 13.28 469 1.73 14.99 470 0.23 0.13 471 0.70 0.24 47215.60 58.59 473 5.76 18.30 474 7.47 26.68 475 32.08 931.87 476 38.8332.20 477 >250 951.52 478 32.11 53.66 479 2.60 9.06 480 >250 1924.30 48126.05 44.41 482 >250 1227.00 483 >250 565.97 484 68.69 179.80 485 >250700.32 486 >250 1009.60 487 27.86 81.03 488 16.91 12.99 489 >250 1676.90490 95.00 463.24 491 >250 1680.00 492 25.64 58.44 493 193.77 836.68 494102.32 290.97 495 >250 747.51 496 64.01 154.23 497 64.50 568.51 49850.67 259.54 499 163.43 500.79 500 107.96 457.00 501 20.86 108.40 5029.06 44.35 503 5.22 5.47 504 6.78 5.62 505 5.61 10.05 506 8.82 8.67 5079.83 19.68 508 14.99 29.01 509 49.53 90.08 510 245.60 382.06 511 >250431.47 512 >250 1137.50 513 >250 933.78 514 212.47 269.01 515 1.72228.47 516 3.17 12.75 517 5.23 21.35 518 5.50 19.62 519 6.58 18.33 52043.78 420.57 521 33.30 222.54 522 1.26 23.59 523 1.92 3.96 524 3.7511.02 525 1.54 4.43 526 1.32 1.13 527 5.66 16.31 528 6.25 12.93 529 0.702.25 530 12.45 50.75 531 1.34 11.38 532 4.42 21.46 533 0.78 0.17 5349.80 5.18 535 1.63 0.71 536 3.83 5.05 537 0.42 2.09 538 11.51 48.93 53916.96 83.68 540 0.36 13.52 541 0.55 36.26 542 0.47 11.67 543 1.43 17.35544 1.01 0.13 545 0.40 0.22 546 1.23 0.69 547 0.31 0.13 548 0.63 0.13549 0.99 0.28 550 1.67 0.83 551 0.24 0.13 552 2.76 15.20 553 1.39 6.89554 1.57 12.00 555 13.26 266.85 556 3.41 13.95 557 1.71 9.73 558 2.8720.44 559 0.97 7.77 560 0.85 2.86 561 0.71 3.06 562 0.97 2.64 563 0.6610.63 564 2.53 31.30 565 1.98 9.24 566 0.78 4.46 567 1.73 7.93 568 2.848.10 569 6.66 11.16 570 0.80 0.84 571 30.40 62.31 572 25.28 93.92 5731.21 7.46 574 0.73 17.30 575 57.08 141.99 576 2.05 6.90 577 19.55 81.16578 160.78 1867.50 579 19.12 110.87 580 1.63 5.79 581 0.89 2.16 582 4.9615.61 583 2.63 9.53 584 0.91 2.98 585 0.69 1.90 586 0.85 2.94 587 23.3366.14 588 0.69 2.33 589 0.63 2.56 590 1.05 2.04 591 0.72 0.17 592 96.22773.99 593 7.24 33.00 594 0.58 0.12 595 1.27 0.52 596 0.70 0.14 597 2.795.93 598 1.11 0.11 599 2.38 41.16 600 2.59 6.64 601 1.16 0.17 602 0.930.53 603 1.94 0.09 604 0.83 0.12 605 1.26 0.12 606 3.08 2.42 607 0.900.23 608 2.36 0.48 609 2.36 0.39 610 0.37 0.23 611 0.40 0.07 612 6.061.02 613 0.58 0.71 614 2.06 0.13 615 1.54 0.28 616 2.30 0.20 617 0.780.22 618 0.34 0.13 619 0.95 0.14 620 1.22 0.07 621 1.32 0.32 622 2.8727.26 623 2.27 22.03 624 5.81 0.32 625 2.47 10.12 626 5.16 0.26 6272.57 >50 628 0.73 0.23 629 0.20 0.05 630 0.32 0.08 633 1.55 7.08 6345.19 38.98 635 2.08 2.75 636 0.34 0.13 637 2.06 0.39 639 2.42 0.58 6401.60 0.12 641 77.54 206.57 642 37.83 153.96 643 36.42 98.88 644 >2501416.80 645 48.95 79.64 646 >250 338.27 647 128.54 233.79 648 >2501947.60 649 11.75 21.72 650 6.86 18.76 651 128.75 480.48 652 19.56 79.60653 25.34 129.75 654 54.53 133.41 655 40.37 253.74 656 10.14 56.95 65781.34 226.69 658 1.87 7.88 659 3.98 38.15 660 6.05 33.57 661 4.68 25.48662 19.16 88.62 663 24.53 159.53 664 0.92 0.21 665 1.46 2.79 666 1.802.80 667 100.42 413.82 668 >250 857.30 669 >250 690.37 670 154.42 572.73671 >250 1618.60 672 147.66 382.84 673 5.46 31.58 674 16.34 48.11 67549.50 78.74 676 141.12 429.31 677 12.23 22.24 678 23.86 38.83 679 67.92124.25 680 224.61 453.73 681 61.26 94.03 682 1.59 17.89 683 1.31 10.87684 1.29 5.84 685 >250 551.08 686 45.03 285.26 687 8.72 53.47 688 7.0234.16 689 3.02 10.59 690 12.70 21.94 691 43.34 348.80 692 3.20 23.15 6939.78 49.41 694 0.61 0.23 695 1.82 17.44 696 0.51 105.12 697 0.65 0.27698 3.84 0.81 699 3.15 0.56 700 4.37 0.54 701 3.04 2.56 702 1.70 0.26703 1.24 0.14 704 0.73 0.36 705 0.40 0.07 706 0.33 0.15 707 2.65 8.88708 3.30 6.21 709 1.24 0.40 710 1.43 4.06 713 NA 0.39 714 0.70 0.19 7151.42 0.32 716 0.35 0.28 717 0.69 0.26 718 3.07 0.33 719 0.51 0.46 7210.77 0.32 722 1.10 0.58 723 2.75 1.04 732 2.66 2.52 733 2.72 0.11 7341.69 0.19 735 2.94 0.38 736 1.91 0.21 737 1.79 0.18 738 1.74 0.21 7400.61 0.28 741 0.49 0.68 745 0.62 0.69 746 2.37 0.84 748 2.50 1.76 NA:not available

Although the foregoing invention has been described in some detail byway of illustration and Example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20240043427A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein Y is a bond,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—,—C₁₋₆alkyl-O—C₁₋₆alkyl, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-O—,—C₃₋₇cycloalkyl-O—, —O—C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl-C₁₋₃alkyl,—S(═O)₂—, —S(═O)₂CH₂—, —CH₂S(═O)₂—, —N(R^(a))—, —N(R^(a))CH₂—,—C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—, —C₁₋₃alkylN(R^(a))C(═O)—,heterocycloalkyl-C(═O)—, heterocycloalkyl-N(H)C(═O)—, heterocycloalkyl,heterocycloalkyl-C₁₋₆alkyl-O—, or heterocycloalkyl-O—, wherein eachalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted withone to four halogens and is further optionally substituted with one ortwo groups independently selected from —CN, —C₁₋₃alkyl and—C₁₋₃haloalkyl; one or two of Z¹, Z² and Z³ is CR² and the remaining oneor two of Z¹, Z², and Z³ is N; one of W¹ and W² is N and the other is C;R¹ is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl,—C₁₋₆alkyl-C₆₋₁₂aryl, —C₁₋₆alkyl-heteroaryl, heterocycloalkyl,heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl,aryl, heterocycloalkyl, or heteroaryl is optionally substituted with oneto three halogens and is further optionally substituted with one or twoR³; R² is each independently hydrogen, halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)heterocycloalkyl,—C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))heteroaryl,—C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆₋₁₂aryl, —N(R^(b))(R^(b)),—C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with one to three halogens and is further optionallysubstituted with one to three R⁴; R³ is halogen, —CN, —C₁₋₆alkyl,—C₃₋₇cycloalkyl, —C₁₋₃alkyl-C₃₋₇cycloalkyl, —C₁₋₃alkyl-heterocycloalkyl,—N(R^(b))(R^(b)), —N(H)C(═O)O—R^(c), —C(═O)N(R^(b))(R^(b)),—C(═O)OC₁₋₆alkyl, —C(═O)OC₁₋₆alkylC₆₋₁₂aryl, —C(═O)C₁₋₃alkyl,—C(═O)C₃₋₇cycloalkyl, —C(═O)heterocycloalkyl, —OC(═O)heterocycloalkyl,—OC(═O)N(H)C₁₋₆alkyl, —OC(═O)N(H)C₃₋₇cycloalkyl, —OC(═O)OC₁₋₆alkyl,—OC(═O)N(H)C₆₋₁₂aryl, or —OR^(c), wherein each alkyl, cycloalkyl,heterocycloalkyl, or aryl is optionally substituted with one to threehalogens and is further optionally substituted with one or two R^(c); R⁴is halogen, —CN, —OR^(c), —C₁₋₆alkyl, —N(R^(b))(R^(b)), or—C₁₋₆haloalkyl; R^(a) is each independently hydrogen, or —C₁₋₃alkyl;R^(b) is each independently hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,—C₁₋₆alkyl-C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl-C₁₋₆haloalkyl,—C₃₋₇cycloalkyl, —C₃₋₇halocycloalkyl, or —C(═O)C₁₋₆alkyl; and R^(c) iseach independently hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,—C₃₋₇cycloalkyl, —C₁₋₃alkyl-C₃₋₇cycloalkyl,—C₁₋₃alkyl-C₃₋₇cyclohaloalkyl, —OC₁₋₆alkyl, or —C₃₋₇halocycloalkyl; andwherein each heterocycloalkyl or heteroaryl bears one to fourheteroatoms each independently selected from N, O, and S; wherein eachheterocycloalkyl has 4 to 15 ring members; and wherein each heteroarylhas 5 to 15 ring members.
 2. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein Y is a bond,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—,—C₁₋₆alkyl-O—C₁₋₆alkyl, —O—C₁₋₆alkyl, —C₃₋₇cycloalkyl-O—,—O—C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl-C₁₋₃alkyl, —S(═O)₂—, —S(═O)₂CH₂—,—CH₂S(═O)₂—, —N(R^(a))—, —N(R^(a))CH₂—, —C₁₋₆alkyl-N(R^(b))—,—C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—, —C₁₋₃alkylN(R^(a))C(═O)—,heterocycloalkyl-C(═O)—, heterocycloalkyl or heterocycloalkyl-O—,wherein each alkyl, cycloalkyl, or heterocycloalkyl is optionallysubstituted with one to four halogens and is further optionallysubstituted with one or two groups independently selected from —CN and—C₁₋₃alkyl; one or two of Z¹, Z² and Z³ is CR² and the remaining one ortwo of Z¹, Z², and Z³ is N; one of W¹ and W² is N and the other is C; R¹is hydrogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆₋₁₂aryl,heterocycloalkyl, heteroaryl, or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein eachalkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionallysubstituted with one to three halogens and is further optionallysubstituted with one or two R³; R² is each independently hydrogen,halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),—C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))heteroaryl,—C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)),—C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with one to three halogens and is further optionallysubstituted with one to three R⁴; R³ is halogen, —CN, —C₁₋₆alkyl,—C₁₋₆haloalkyl, —C₃₋₇cycloalkyl, —N(R^(b))(R^(b)), —C(═O)OC₁₋₆alkyl,—OC(═O)N(H)C₁₋₆alkyl, —OC(═O)OC₁₋₆alkyl, or —OR^(c); R⁴ is halogen, —CN,—OR^(c), —C₁₋₆alkyl, —N(R^(b))(R^(b)), or —C₁₋₆haloalkyl; R^(a) is eachindependently hydrogen, or —C₁₋₃alkyl; R^(b) is each independentlyhydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₁₋₆alkyl-C₃₋₇cycloalkyl,—C₃₋₇cycloalkyl, —C₃₋₇halocycloalkyl, or —C(═O)C₁₋₆alkyl; and R^(c) iseach independently hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,—C₃₋₇cycloalkyl, or —C₃₋₇halocycloalkyl; and wherein eachheterocycloalkyl or heteroaryl bears one to four heteroatoms eachindependently selected from N, O, and S; wherein each heterocycloalkylhas 4 to 10 ring members; and wherein each heteroaryl has 5 to 10 ringmembers.
 3. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —O—C₁₋₆alkyl,—C₃₋₇cycloalkyl-O—, —O—C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl-C₁₋₃alkyl-,—S(═O)₂—, —S(═O)₂CH₂—, —CH₂S(═O)₂—, —N(R^(a))—, —N(R^(a))CH₂—,—C₁₋₆alkyl-N(R^(b))—, —C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—,—C₁₋₃alkylN(R^(a))C(═O)—, heterocycloalkyl-C(═O)—, —O—C₁₋₆alkyl-O—,heterocycloalkyl-N(H)C(═O)—, heterocycloalkyl-C₁₋₆alkyl-O—, orheterocycloalkyl, wherein each alkyl, cycloalkyl, or heterocycloalkyl isoptionally substituted with one to four halogens and is furtheroptionally substituted with one or two groups independently selectedfrom —CN—C₁₋₃alkyl and —C₁₋₃haloalkyl; R¹ is hydrogen, —CN, —C₁₋₆alkyl,—C₃₋₇cycloalkyl, —C₆₋₁₂aryl, —C₁₋₆alkyl-C₆₋₁₂aryl,—C₁₋₆alkyl-heteroaryl, heterocycloalkyl, heteroaryl, or—C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl, aryl,heterocycloalkyl, or heteroaryl is optionally substituted with one tothree halogens and is further optionally substituted with one or two R³;R³ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,—C₁₋₃alkyl-C₃₋₇cycloalkyl, —C₁₋₃alkyl-heterocycloalkyl,—N(R^(b))(R^(b)), —N(H)C(═O)O—R^(c), —C(═O)N(R^(b))(R^(b)),—C(═O)OC₁₋₆alkylC₆₋₁₂aryl, —C(═O)C₁₋₃alkyl, —C(═O)C₃₋₇cycloalkyl,—C(═O)heterocycloalkyl, —OC(═O)heterocycloalkyl,—OC(═O)N(H)C₃₋₇cycloalkyl, —OC(═O)N(H)C₆₋₁₂aryl, or —OR^(c); R^(b) iseach independently hydrogen, —C₁₋₆alkyl, —C₁₋₆haloalkyl,—C₃₋₇cycloalkyl, —C₃₋₇halocycloalkyl, or —C(═O)C₁₋₆alkyl.
 4. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Y is a bond, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₇cycloalkyl, —C₁₋₆alkyl-O—, —O—C₁₋₆alkyl, —C₃₋₇cycloalkyl-O—,—O—C₃₋₇cycloalkyl, —C₃₋₇cycloalkyl-C₁₋₃alkyl-, —S(═O)₂—, —S(═O)₂CH₂—,—CH₂S(═O)₂—, —N(R^(a))—, —N(R^(a))CH₂—, —C₁₋₆alkyl-N(R^(b))—,—C₃₋₇cycloalkyl-N(R^(b))—, —N(R^(a))C(═O)—, —C₁₋₃alkylN(R^(a))C(═O)—,heterocycloalkyl-C(═O)—, or heterocycloalkyl, wherein each alkyl,cycloalkyl, or heterocycloalkyl is optionally substituted with one tofour halogens and is further optionally substituted with one or twogroups independently selected from —CN and —C₁₋₃alkyl; R¹ is hydrogen,—CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₆aryl, heterocycloalkyl, heteroaryl,or —C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl, aryl,heterocycloalkyl, or heteroaryl is optionally substituted with one tothree halogens and is further optionally substituted with one or two R³;R³ is halogen, —CN, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl,—N(R^(b))(R^(b)), or —OR^(c); R^(b) is each independently hydrogen,—C₁₋₆alkyl, —C₁₋₆haloalkyl, —C₃₋₇cycloalkyl, —C₃₋₇halocycloalkyl, or—C(═O)C₁₋₆alkyl.
 5. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (II-a):

wherein R^(2a) and R^(2b) are each independently hydrogen, halogen, —CN,—C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),—C(═O)heterocycloalkyl, —C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))(R^(b)),—C₁₋₆alkyl-S(═O)₂C₆₋₁₂aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl,heterocycloalkyl, or heteroaryl, wherein each alkyl, cycloalkyl,heterocycloalkyl, aryl, or heteroaryl is optionally substituted with oneto three halogens and is further optionally substituted with one tothree R⁴.
 6. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, having the structure of Formula (II-a):

wherein R^(2a) and R^(2b) are each independently hydrogen, halogen, —CN,—C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),—C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl,—N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, whereineach alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl isoptionally substituted with one to three halogens and is furtheroptionally substituted with one to three R⁴.
 7. The compound of claim 1,or a pharmaceutically acceptable salt thereof, having the structure ofFormula (II-b):

wherein R^(2b) is hydrogen, halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl,—O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl,—C(═O)N(R^(b))heteroaryl, —C(═O)N(R^(b))(R^(b)),—C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl,or heteroaryl, wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl,or heteroaryl is optionally substituted with one to three halogens andis further optionally substituted with one to three R⁴.
 8. The compoundof claim 1 or a pharmaceutically acceptable salt thereof, having thestructure of Formula (II-c):

wherein R^(2a) and R^(2b) are each independently hydrogen, halogen, —CN,—C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a),—C(═O)N(R^(b))C₆₋₁₂aryl, —C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl,—N(R^(b))(R^(b)), —C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, whereineach alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl isoptionally substituted with one to three halogens and is furtheroptionally substituted with one to three R⁴.
 9. The compound of claim 1,or a pharmaceutically acceptable salt thereof, having the structure ofFormula (II-d):

wherein R^(2a) is hydrogen, halogen, —CN, —C₁₋₆alkyl, —C₃₋₁₀ cycloalkyl,—O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl,—C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)),—C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with one to three halogens and is further optionallysubstituted with one to three R⁴.
 10. The compound of claim 1, or apharmaceutically acceptable salt thereof, having the structure ofFormula (II-e):

wherein R^(2a) is independently hydrogen, halogen, —CN, —C₁₋₆alkyl,—C₃₋₁₀ cycloalkyl, —O—C₁₋₆alkyl, —C(═O)OR^(a), —C(═O)N(R^(b))C₆₋₁₂aryl,—C(═O)N(R^(b))(R^(b)), —C₁₋₆alkyl-S(═O)₂C₆aryl, —N(R^(b))(R^(b)),—C₆₋₁₂aryl, heterocycloalkyl, or heteroaryl, wherein each alkyl,cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionallysubstituted with one to three halogens and is further optionallysubstituted with one to three R⁴.
 11. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is —C₁₋₆alkyl,—C₃₋₇cycloalkyl, —C₆₋₁₂aryl, heterocycloalkyl, heteroaryl, or—C₁₋₆alkyl-O—C₁₋₆alkyl, wherein each alkyl, cycloalkyl, aryl orheteroaryl is optionally substituted with one to three halogens and isfurther optionally substituted with one or two R³.
 12. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ isisopropyl, —F, —CF₃, pyrrolidinyl, morpholinyl, imidazolyl, phenyl,pyridinyl, —CH₂OCH₃, —C(CH₃)₃, cyclopropyl or


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R¹ is


14. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R², R^(2a) and R^(2b) are each independently hydrogen,halogen, C₁₋₆alkyl, C₃₋₁₀cycloalkyl, —C(═O)OR^(a),—C₁₋₆alkyl-S(═O)₂C₆aryl, heteroaryl or C₆aryl, wherein each alkyl,cycloalkyl, or aryl is optionally substituted with one to three halogensand is further optionally substituted with one or two R⁴.
 15. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R², R^(2a), and R^(2b) are each independently —H, —F, —CH₃,—CH₂CH₃, —CF₃, phenyl, —CH₂SO₂Ph, —C(═O)OCH₂CH₃, cyclopropyl, or


16. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R², R^(2a), and R^(2b) are each CN,


17. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R², R^(2a), and R^(2b) are each


18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R³ is —CH₃, —CH₂CH₃, —F, —Cl, —CF₃, cyclopropyl, —OCF₃or —CN.
 19. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein R³ is —O—CH₃ or


20. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁴ is —F or —CF₃.
 21. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Y is a bond.
 22. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Y—R¹ is: —CH₃, —CH₂CH₃, isopropyl, —O-isopropyl, —OPh,


23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Y—R¹ is:


24. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Y—R¹ is:


25. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the structure of Formula (II-f):

wherein R¹ is phenyl or heteroaryl, each of which is optionallysubstituted with one to three halogens and is further optionallysubstituted with one or two R³, R^(2a) and R^(2b) are each independentlyhydrogen or halogen.
 26. The compound of claim 25, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (III-a):


27. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the structure of Formula (II-g):

wherein R¹ is phenyl or heteroaryl, each of which is optionallysubstituted with one to three halogens and is further optionallysubstituted with one or two R³, R^(2a) and R^(2b) are each independentlyhydrogen or halogen.
 28. The compound of claim 27, or a pharmaceuticallyacceptable salt thereof, having the structure of Formula (III-b):


29. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the structure of Formula (II-h):

wherein R¹ is C₃₋₇cycloalkyl or heterocycloalkyl, each of which isoptionally substituted with one to three halogens and is furtheroptionally substituted with one or two R³, R^(2a) and R^(2b) are eachindependently hydrogen or halogen.
 30. The compound of claim 1, or apharmaceutically acceptable salt thereof, having the structure ofFormula

wherein each R⁵ is independently halogen, —CN, —C₁₋₆alkyl,—C₃₋₇cycloalkyl, —C₁₋₆alkyl-N(R^(d))(R^(d)), —OR^(c), —N(R^(b))(R^(b)),—C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —OC(═O)N(H)C₁₋₆alkyl,—OC(═O)OC₁₋₆alkyl, —O—C₆₋₁₂aryl, —O-heteroaryl, or —C₁₋₆haloalkyl, orthe two R⁵ moieties join together to form a 3 to 6 membered cycloalkylor heterocycloalkyl ring, wherein the ring is optionally substitutedwith one to three halogens and is further optionally substituted withone to three R⁶; R⁶ is halogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl,—N(R^(b))(R^(b)), —C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl,—OC(═O)N(H)C₁₋₆alkyl, —OC(═O)OC₁₋₆alkyl, or —OR^(c); and m is 0, 1, 2, 3or
 4. 31. The compound of claim 1, or a pharmaceutically acceptable saltthereof, having the structure of Formula

wherein each R⁵ is independently halogen, —CN, —C₁₋₆alkyl,—C₃₋₇cycloalkyl, —C₁₋₆alkyl-N(R^(d))(R^(d)), —OR^(c), —N(R^(b))(R^(b)),—C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —OC(═O)N(H)C₁₋₆alkyl,—OC(═O)OC₁₋₆alkyl, or —C₁₋₆haloalkyl, or the two R⁵ moieties jointogether to form a 3 to 6 membered cycloalkyl or heterocycloalkyl ring,wherein the ring is optionally substituted with one to three halogensand is further optionally substituted with one to three R⁶; R⁶ ishalogen, —CN, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —N(R^(b))(R^(b)),—C(═O)C₁₋₆alkyl, —C(═O)OC₁₋₆alkyl, —OC(═O)N(H)C₁₋₆alkyl,—OC(═O)OC₁₋₆alkyl, or —OR^(c); and m is 0, 1, 2, 3 or
 4. 32. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,having the structure of Formula

wherein R^(7a), R^(7b), R^(7c), and R^(7d) are independently halogen,—C₁₋₆alkyl or —C₁₋₆haloalkyl, or the two of the R^(7a), R^(7b), R^(7c),or R^(7d) moieties join together to form a 3 to 6 membered cycloalkylring, wherein the ring is optionally substituted with one to threehalogens.
 33. The compound of claim 1 wherein the compound is selectedfrom the compounds of Table 2, or a pharmaceutically acceptable saltthereof.
 34. A pharmaceutical composition comprising a compound of claim1, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 35. The pharmaceutical composition ofclaim 34, further comprising one or more additional therapeutic agents.36. The pharmaceutical composition of claim 35, wherein the additionaltherapeutic agent is independently an anti-neoplastic agent,chemotherapy, radiation therapy, or resection therapy.
 37. Thepharmaceutical composition of claim 35, wherein the additionaltherapeutic agent is independently rituxan, doxorubicin, gemcitabine,nivolumab, pembrolizumab, nivolumab, atezolizumab or ipilimumab.
 38. Thepharmaceutical composition of claim 35, wherein the additionaltherapeutic agent is a PD-1/PD-L1 inhibitor.
 39. A method of inhibitingCD73 in a subject in need thereof, the method comprising administeringto the subject a therapeutically effective amount of a compound of anyone of claims 1-33, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition of any one of claims 34-38.
 40. A method oftreating cancer in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of any one of claims 1-33, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition of any one of claims34-38.
 41. The method of claim 40, wherein the cancer is pancreaticcancer, bladder cancer, colorectal cancer, breast cancer, prostatecancer, renal cancer, hepatocellular cancer, lung cancer, ovariancancer, cervical cancer, gastric cancer, esophageal cancer, head andneck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain cancer,bone cancer, soft tissue sarcoma, non-small cell lung cancer, small-celllung cancer, thyroid cancer, or colon cancer.
 42. The method of claim40, wherein the cancer is acute lymphocytic leukemia (ALL), acutemyeloid leukemia (AML), chronic lymphocytic leukemia (CLL), smalllymphocytic lymphoma (SLL), myelodysplastic syndrome (MDS),myeloproliferative disease (MPD), chronic myeloid leukemia (CML),multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), mantle celllymphoma (MCL), follicular lymphoma, Waldestrom's macroglobulinemia(WM), T-cell lymphoma, B-cell lymphoma, or diffuse large B-cell lymphoma(DLBCL).
 43. The method of any one of claims 39-42, further comprisingadministering one or more additional therapeutic agents to the subject.44. The method of claim 43, wherein the additional therapeutic agent isindependently an anti-neoplastic agent, nivolumab, pembrolizumab,atezolizumab, ipilimumab, chemotherapy, radiation therapy, or resectiontherapy.
 45. The method of claim 43, wherein the additional therapeuticagent is independently rituxan, doxorubicin, gemcitabine, nivolumab,pembrolizumab, nivolumab, atezolizumab, or ipilimumab.
 46. The method ofclaim 43, wherein the additional therapeutic agent is a PD-1/PD-L1inhibitor.
 47. The method of claim 43, wherein the one or moreadditional therapeutic agent comprises one or more populations of immunecells selected from the group consisting of: natural killer (NK) cells,NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage(MAC) cells, tumor infiltrating lymphocytes (TILs), and dendritic cell(DCs).
 48. The method of claim 43, wherein the one or more additionaltherapeutic agent comprises a population of T cells selected from thegroup consisting of: alpha/beta TCR T cells, gamma/delta TCR T cells,regulatory T (Treg) cells, and TRuC™ T cells.
 49. The method of claim43, wherein the one or more additional therapeutic agent comprises apopulation of NK-92 cells.
 50. The method of claim 47, wherein the oneor more populations of immune cells comprise one or more chimericantigen receptors (CARs).
 51. The method of any one of claims 47-49,wherein the cells are allogeneic to an intended recipient.
 52. Themethod of claim 43, wherein the one or more additional therapeuticagents comprises an immunotherapy, an immunostimulatory therapy, acytokine therapy, a chemokine therapy, a cellular therapy, a genetherapy, or combinations thereof.
 53. The method of claim 52, whereinthe immunotherapy comprises co-administering one or more antibodies orantigen-binding antibody fragments thereof, or antibody-drug conjugatesthereof, CD3-targeting multi-specific molecules, CD16-targetingmulti-specific molecules, or non-immunoglobulin antigen-binding domainsor antibody mimetic proteins directed against one or more targets ortumor associated antigens (TAAs). 54-60. (canceled)